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Microenvironmental influences on T cell immunity in cancer and inflammation

Microenvironmental influences on T cell immunity in cancer and inflammation www.nature.com/cmi REVIEW ARTICLE OPEN Microenvironmental influences on T cell immunity in cancer and inflammation 1,3 1,3 1,2 Darren R. Heintzman , Emilie L. Fisher and Jeffrey C. Rathmell © The Author(s), under exclusive licence to CSI and USTC 2022 T cell metabolism is dynamic and highly regulated. While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns, the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways. T cells must function in a wide variety of tissue settings, and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance. Both in inflamed and cancer tissues, a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity. These include fever and increased temperatures, depletion of critical micro and macro- nutrients, and accumulation of inhibitory waste products. Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity. Keywords: immunometabolism; T cell; microenvironment; cancer; inflammation Cellular & Molecular Immunology (2022) 19:316–326; https://doi.org/10.1038/s41423-021-00833-2 INTRODUCTION microenvironment exerts a profound influence on these processes. The classic metabolic chart present in every biology classroom and Cell activating signals, microenvironmental nutrients, and other textbook is a staple of biochemical training and represents the conditions integrate through upregulation of nutrient transporters culmination of over a century of detailed and rigorous studies. and the subsequent changes in intracellular nutrients influence cell These seminal discoveries define the landscape of fundamental bioenergetics, biosynthesis, and signaling. Metabolic signaling chemical reactions that integrate environmental signals and through generation of co-factors or posttranslational modifications nutrients to support the viability, growth, and activities of every can then serve to shape cell fate or activate metabolic checkpoints. living cell. When cells receive signals to perform specific functions These include nutrient sensing pathways such as the AMPK or such as to grow and proliferate, they adjust their nutrient uptake mTORC1 and HIF signaling axis, stress response pathways and shift metabolic programs to meet the new demands. If, including reactive oxygen species (ROS) and ER stress, or changes however, adequate levels of essential nutrients are not available or to epigenetic marks and histone modifications that regulate gene if end products or waste products accumulate, basic chemistry and expression. These changes are broadly relevant to immunity and chemical equilibriums may bring these pathways to a halt or shift inflammation and may have a particularly important impact in their outcomes to disrupt or alter cell fates. Thermodynamic effects settings such as obesity or in tumor microenvironments (TME). such as temperature changes may also influence T cells. Much the Here we review how key changes in systemic nutrient status as same as cell cycle checkpoints can stop or delay cell division, well as microenvironmental metabolites and other conditions are metabolic checkpoints thus interpret nutrients and cell energetics integrated to shape the fate of T cells. to determine cell differentiation, function, and fate. Cell metabo- lism is thus the biochemistry of how cells interpret and integrate Micronutrients and ions signals from their microenvironment. While cell metabolism typically focuses on intermediary metabo- T cells and macrophage metabolism have been studied to the lites and central carbon metabolism pathways, ions and other greatest detail in the field of immunometabolism. In addition to elements play key roles (Fig. 1A). Micronutrients such as ions have many studies focused on how cell activation signals can reprogram increasingly been shown to impact the adaptive immune system, metabolism from catabolic programs designed to generate energy particularly T cells. For example, recent literature has highlighted + + to anabolic programs that efficiently provide biosynthetic pre- that potassium (K ) can directly influence T cells. Increased K ion cursors to support cell growth and proliferation [1], it is now concentration in the tumor microenvironment can acutely silence apparent that each immune cell type and subset has specific T cell effector function [2]. In contrast, high concentrations of this metabolic requirements for activation and differentiation that ion preserve T cell stemness through acetyl CoA metabolism reflect their specific roles and demands. Importantly, the tissue and by epigenetically regulating gene transcription, nutrient 1 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37205, USA. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37205, USA. These authors contributed equally: Darren R. Heintzman, Emilie L. Fisher. email: jeff.rathmell@vumc.org Received: 15 December 2021 Accepted: 19 December 2021 Published online: 17 January 2022 1234567890();,: D.R. Heintzman et al. Fig. 1 Chemical and physical components of the tissue microenvironment that can modulate immunity. A Changes to micronutrients, including iron and potassium, regulate T cell function and survival from ferroptosis. B Increased H + and decreased pH also play important roles in T cell metabolism and fate. C Fever and high temperatures directly impact T cells to promote inflammatory states processing, and metabolism [3]. K promoted induction of incidence of disease associated with high salt intake seems to be a mitochondrial AcCoA synthetase 1, promoting mitochondrial shift in T cell differentiation toward the Th17 subset [12, 14–16]. metabolism, a metabolic feature of memory T cells. While these Th17 differentiation in high salt conditions occurs by influencing studies focused on K in the tumor microenvironment, ionic transcriptional networks during differentiation. NFAT5 and its concentrations not limited to potassium have been shown to downstream kinase SGK1 seem to be critical for an anti- produce interesting cellular phenotypes in T cells in various tissue inflammatory switch in Th17 cells [17, 18]. In contrast, high salt settings. Therefore, the ionic composition of tissues represents a has a more nuanced effect on regulatory T cells subsets. Studies relatively unexplored determinant of T cell polarization and T cell have suggested that while induced CD4( + ) Foxp3(+) regulatory effector functions. T cells are not affected in development or function by high salt H concentration is a measure of acidity in tissues and high [19], thymically derived regulatory T cells can become less concentrations of H ions may be due to hypoxic conditions and suppressive [20]. Recently, NaCl has also been suggested to be an increased abundance of cells utilizing aerobic glycolysis and an ionic checkpoint for human Th2 differentiation [21], further secreting lactate [4]. Most studies on acidity and T cell function supporting a diverse role in the differentiation and function of have been focused on the TME and how increased lactate, and T cells. While NaCl has not been well studied in terms of its effect presumably acidic conditions, in the extracellular environment on T cell metabolic programs, one may speculate that metabolic may inhibit effector T cell functions in solid tumors. A major pathways are impacted in T cells by high salt. This is highlighted by consequence of low acidity seems to be through negative effects the similarities between SGK1 and its close relative, Akt, a key on effector cytokine production by T cells, which can be severely driver of the mTORC1 pathway and T cell metabolism [22], and the reduced in acidic conditions [5–7]. Acidity is, however, not only shared activation of these kinases by mTORC2 [23]. These findings, encountered in the TME and inflammatory tissues can experience as well as future studies involving functional and metabolic pH conditions as low as ~5.5 pH [8, 9] (Fig. 1B). Interestingly, a consequences of NaCl, have implications for a wide range of recently published study shows evidence that lymph nodes also chronic inflammatory and autoimmune diseases. harbor highly acidic pH environments that suppress inflammatory Iron (Fe ) has received much attention in recent T cell literature. effector T cell functions in T cell rich zones. In this study, naïve T Iron deposition is a hallmark of many autoimmune diseases cell priming was unaffected, and T cells were able to rapidly including lupus and multiple sclerosis and plays a key role as a co- recover from acid induced inhibition within hours after pH rescue factor for many enzymes, including TCA cycle enzymes that drive [7] such as would occur upon exit from the lymph node. This mitochondrial metabolism. Excess iron, however, can also lead to provided evidence that acidic inhibition of effector functions is generation of ROS through Fenton reactions and lead to the related to changes in metabolic programming, as low pH shifted process of ferroptosis, or iron-dependent cell death. Iron uptake T cells from glycolytic metabolism to oxidative phosphorylation and handling, therefore, must be tightly regulated, and aberrant and mitochondrial metabolism. Future studies involving therapeu- iron metabolism and homeostasis have been recently shown to tic shifts in tissue pH in inflammation and disease may aid in directly influence T cell effector functions. A direct indication of the relieving chronic inflammation and other T cell mediated diseases. role of iron is shown by genetic variants of the iron uptake protein Sodium ions (Na ) also influence T cell differentiation and Transferrin Receptor, (CD71), which are associated with a common function. Peripheral tissues accumulate NaCl in high concentra- variable immune deficiency [24]. CD71 is also a highly dynamic tions in both diet-intake dependent, such as in high-salt western marker of lymphocyte activation and plasmablasts. Iron depriva- style diets, and independent mechanisms [10]. While sodium is a tion can reduce clinical scores in EAE, a T cell dependent disease in vital nutrient, excess salt is associated with higher incidence of mice [25]. Conversely, excess intracellular available iron in CD4 autoimmune diseases such as arthritis, multiple sclerosis, and in T cells was linked to the pathophysiology of SLE through a mouse studies, colitis [11–13]. One explanation for the increased mechanism of altered DNA methylation states favoring enhanced Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. immune-related gene expression [26] and by regulating the through the increased expression of alpha4 integrins and Heat stability of the RNA binding protein Pcbp1 [27]. Ferroptosis can Shock Protein 90 [44]. Other temperature-inducible proteins like play a key role to shape T cell responses. This process is redox heat shock factor-1 (HSF1) are induced at a lower temperature in T mediated and largely identified through the functions of lymphocytes than B lymphocytes (39 °C vs. 42 °C), indicating Glutathione peroxidase 4 (Gpx4), a selenoenzyme that reduces specialized functions of T cells at febrile temperatures [45, 46]. membrane phospholipid hydroperoxides to maintain cellular Several studies suggest temperature changes have significant redox homeostasis [28]. Inactivation or depletion of Gpx4 in a impacts on T cell activation, proliferation, and differentiation. In variety of cell types can induce ferroptosis [29, 30]. A recent study vitro studies suggest that T cell proliferation occurs more rapidly has shown that Tregs require Gpx4 to neutralize lipid peroxides and to a greater extent at febrile temperatures [47]. Elevated and prevent ferroptosis to maintain Treg cell activation and inhibit temperatures have also been shown to reduce costimulatory anti-tumor immunity [31]. In follicular helper T cells (Tfh), inhibition thresholds to T cell activation due to a more fluid lipid bilayer, of ferroptosis by GPX4 also protected cells from cell death in perhaps providing a mechanism to explain elevated proliferation germinal centers [32]. In tumors, CD36-mediated lipid uptake can rates [48]. Recent work has shown that T cell differentiation is also enhance ferroptosis to dampen anti-tumor immunity by promot- influenced by changes in temperature. In a report where naïve CD4 ing lipid peroxidation [33]. T cells were primed in vitro at moderate fever temperatures (39 °C), cells underwent transcriptional reprogramming which enhanced Temperature commitment toward a Th2 phenotype and away from an IFNy A physical feature of tissue microenvironments that can affect producing Th1 phenotype [49]. Interestingly, coculture with thermodynamic regulation of enzymatic rates and cell physiology dendritic cells inhibited this transcriptional transition, suggesting is temperature (Fig. 1C). Temperatures fluctuate extensively in the that cellular composition of the tissue microenvironment can human body, hovering around 37 °C in the core and central influence T cell responses at febrile temperatures. Cellular organs, such as the spleen, to as low as 28 °C in peripheral organs signaling mechanisms have been shown to be altered by changing such as the skin at thermoneutrality [34, 35]. Temperatures also temperatures in other cell types, such as recent work showing that vary widely in response to several physiological and pathophysio- NF-kB signaling is exquisitely temperature dependent in mouse logical mechanisms. Systemically, fevers can arise in many diseases adult fibroblasts and human neuroblastoma cells [50]. An and are a common side effect in bacterial and fungal infections, intriguing paper was recently published focusing on the effects blood borne cancers like lymphoma, and a variety of autoimmune of febrile temperatures on Th17 cell differentiation [51]. These and inflammatory diseases, such as Adult-Onset Stills Disease [36]. studies provided evidence that elevated temperatures predomi- While fevers are responsible for systemically increased tempera- nantly impact Th17 cell differentiation, causing this helper subset tures, localized temperature changes are also common in to enhance IL17a production. Febrile temperatures enhanced the damaged and inflamed tissue regions and have long been pathogenic gene transcription signatures of Th17 cells and caused recognized. As early as the first century B.C., observations were higher neutrophil invasion in bronchoalveolar lavage fluid in a made by Celsius that heat is a cardinal signs of inflammation [37]. mouse model of allergic airway inflammation. This study high- Over 100 years ago, studies showed that after breaking the femur lighted the potential that not only are T cells able to respond of a hamster, local temperatures at the break site rose by as many biochemically to elevated temperatures, but that this biochemical as 1–4 °C compared to non-injured limbs [38]. Interestingly, when response could have T cell-subset specific effects on immunity and ischemia was induced at the site of the break, the local inflammation. temperature rose substantially, arguing that cellular activity at A potential explanation for subset specific adaptation to the site of inflammation was responsible for increased temperature elevated temperature may be metabolic programming and and blood perfusion was necessary to dissipate this heat. These mitochondrial adaptation. Exposure of CD8( + ) T cells to febrile studies have been supported by more modern technological temperatures during activation caused significant enhancement of methodologies such as the use of temperature sensitive ratio- mitochondrial respiration in addition to enhanced extracellular metric dyes [39]. Human biology reflects these findings from mice acidification rates [52]. RNA sequencing (RNA-Seq) of CD8( + ) cells and guinea pigs and is substantiated by several publications exposed to febrile temperatures revealed that many upregulated involving rheumatoid arthritis joints. Even in remission, rheuma- gene pathways involved mitochondrial processes. Enzyme activity toid arthritis patients can exhibit elevated temperatures in increases dramatically as temperature increases, and may predict previously affected joints compared to healthy controls. In fact, increased metabolic rates in T cells at febrile temperatures due to the degree of temperature elevation in RA joints has been shown faster enzymatic reactions [53]. It has been established that Th17 to be a reliable predictive indicator of disease progression [40, 41]. cells can utilize glycolysis at a much higher rate than other T cell To date, the actual cause of locally increased temperatures at subsets[54, 55] and seem to be especially sensitive to temperature sites of inflammation is not well understood. Interestingly, change [51, 55]. Perhaps enzymatic activity involved in glycolysis is mitochondrial metabolism has been suggested to generate large enhanced at febrile temperatures. This remains a poorly under- amounts of heat through ATP hydrolysis, with mitochondria stood yet fundamental feature of inflammation. reaching temperatures close to 50 °C within cells [42]. Notably, UCP1 expression seems to correlate with mitochondrial heat Obesity generation and is highly expressed in brown fat where non- Presently over 671 million adults are classified as obese (BMI > 30 shivering thermogenesis regulates body temperature [43]. One kg/m2) and obesity contributing to a wide range of diseases with could speculate that mitochondrial metabolism conducted by underlying inflammatory components (Fig. 2), including diabetes, immune cell infiltrate in inflammation may be responsible for cardiovascular disease, and cancer [56, 57]. Research on obesity locally increased temperatures, however this has not been tested. has widely examined systemic effects of insulin resistance, but All together, these data suggest that heat generation and thermal adipose tissue of obese individuals was also found to directly characteristics within the tissue microenvironment are highly produce high levels of pro-inflammatory cytokines which influence diverse, and likely important during immune challenge. T cell and macrophage differentiation and pro-inflammatory Even with a wealth of data suggestive of frequent and variable phenotypes, including leptin, TNFα, and IL-6 [58–61]. Cell type temperature change in the tissue microenvironment, the effects of composition in obese tissues can also be dysregulated to favor temperature on immune cell function have received relatively inflammation. Obesity-associated chronic inflammation is asso- modest attention (Fig. 1C). Elevated temperatures have been ciated with an accumulation classically activated “M1” polarized shown to promote T lymphocyte trafficking during infection macrophages (ATMs) in adipose tissues [62, 63], which are highly Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. Fig. 2 Obesity leads to both systemic and local changes to T cell microenvironments. Obesity or weight loss can have striking effects on T cell metabolism in the obesity paradox in which tumors are promoted yet sensitized to anti-PD1 inflammatory and secrete pro-inflammatory cytokines like TNFα been shown to alter Treg cell metabolism and migratory function, [63]. These cells contribute to a potentially hostile environment promoting an effector-like migratory phenotype in Tregs, and which can shift the balance of immune cells toward a pro- biased migration toward sites of inflammation through a mechan- inflammatory phenotype. Trem2(+) Lipid Associated Macrophages ism of decreased mTORC1 signaling and increased fatty acid [64] are also implicated and associated with adipocyte hypertro- oxidation [72]. Recently, Tregs were shown to be critical to adipose phy, inflammation, and systemic metabolic dysregulation. While tissue homeostasis, inhibiting white adipose tissue beiging macrophages are prominent inflammatory sources in adipose through secretion of IL-10 regulated by Blimp1 expression [73]. tissue, mediators of macrophage and T cell polarization in adipose Interestingly, Treg-specific loss of IL-10 resulted in increased insulin tissue can seemingly promote either pro- or anti-inflammatory sensitivity and reduced obesity in high-fat diet-fed male mice, phenotypes and include adipokines, fatty acids, and cytokines in suggesting that Tregs may promote healthy obesity in some the tissue microenvironment. The adipokine leptin, which is settings. Together, these studies suggest that regulatory T cells secreted in proportion to adipocyte mass [65], upregulates the play a unique yet currently poorly understood role in obesity. expression of Glut1 in T cells to promote increased glucose uptake The immunological consequences of obesity have been well and glycolysis in T cells, fueling the expansion of T effector cells studied in terms of response to viral infections. In the recent like Th1 and Th17 subsets [66]. Anti-inflammatory adipokines like COVID-19 pandemic, obese individuals have been noted to be Adiponectin are also present in obese adipose tissue and have hospitalized with COVID-19 at a much higher rate than lean been shown to limit these effector cell populations by restricting individuals [74]. Similarly, obesity has been shown to impair the cell intrinsic glycolysis [67]. A constant battle thus maintains adaptive immune system in response to Influenza virus [75]. homeostasis within obese tissues, and dysregulation can cause Recent work has shown that T cells within obese tissue become meaningful swings in the outcomes of T cell differentiation and easily exhausted through upregulation of PD-1 [76], and that PD-1 function. blockade can reverses T cell priming impairments seen in obesity A key determinant of pro- or anti-inflammatory adipose [77]. While reversing PD-1 mediated exhaustion can be beneficial microenvironments is the frequency of regulatory T cells. Obese in terms of rescuing the adaptive response to viral infections, this adipose tissue seems to become a progressively hostile environ- could also increase the risk of autoimmune disorders in obese ment for regulatory T cells, as they are highly present in lean individuals. Many of the inhibitory responses in T cells due to adipose, but numbers decrease in obese adipose tissue [68]. Other obesity can be linked to T cell metabolism. Elevated saturated fatty studies have suggested that circulating regulatory T cells are also acids increase T cell antigen responses and signaling through the reduced in obesity [69]. One explanation for this is that regulatory PI3K/Akt axis to fuel fatty acid oxidation in metabolically stressed T cells can be negatively influenced by adipokines like leptin, environments [78, 79]. Obesity can also result in increased T cell which cause regulatory T cell numbers to be reduced due to the oxygen consumption and less effective response to pathogens, upregulation of glycolysis [66, 70, 71]. However, dietary lipids have and that loss of weight and return to lean state does not rescue Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. this metabolic change in T cells [80]. Activated CD4 + T cells from obese mice had increased glucose uptake and oxygen consump- tion rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose [81]. Interestingly, treatment of obese mice with metformin improved T cell responses to influenza and led to increased rates of survival. Weight loss did not, however, rescue the defects in influenza response. Why weight loss does not result in the rescue of T cell dysfunction in obesity is not well understood, but epigenetic factors associated with obesity may alter T cell chromatin dynamics, creating a seemingly irreversible metabolic shift toward higher mitochondrial respiration and worse outcomes to influenza infections. Future work in this area will be of keen interest and may identify mechanisms involved in metabolic reprogramming of T cells in obesity. Fig. 3 The tumor microenvironment and metabolic immune suppres- Obesity, cancer, and the immunotherapy obesity paradox sion. Obesity leads to chronic systemic and local inflammation. In addition to important considerations of diabetes and heart Adipose-resident CD8 T cells can be more naïve but are also sensitized disease, it is becoming increasingly clear that obesity is associated to reactivate with PD-1 blockade. Many factors contribute to this with cancer incidence and mortality. In this section we will focus obesity paradox, including elevated lactate, decreased glucose, and on how these factors alter the local TME (Fig. 2). The pro- altered amino acids tumorigenic mechanisms behind obesity are multifactorial and include direct effects of systemic hormones and nutrients on the macrophages with increased potential to drive inflammation [98]. cancer cells [82]. Chronic inflammation, long-chain fatty acid Consistent with a pro-inflammatory role for leptin, treatment of metabolism, and consumption of high fructose corn syrup have all lean mice with leptin was sufficient to increase anti-tumor been implicated to directly promote tumorigenesis, independent immunity to an extent similar to PD-1 blockade [87]. Clearly, of their alterations to the anti-tumor immune response [83–85]. obesity and hormones such as leptin play complex roles in the This adds complexity in elucidating the mechanisms involved in TME. Given the prevalence of obesity and the potential for new altering the tumor vs immune system balance and may help insight from obesity that may improve immunotherapy in lean explain differences observed by groups in the field. Single cell individuals, however, makes this an exciting and important area for RNA-Seq studies of changes to immune cell populations in tumors further discovery. of lean and obese mice have shown a variety of potentially impactful changes [86, 87]. Ringel et al. showed that obesity led to The tumor microenvironment increased tumor growth that was particularly apparent in TMEs are heterogeneous and composed of mixed cell types, immunocompetent mice and that tumors from obese mice had nutrients, and stroma that can present a metabolically hostile setting decreased abundance of tumor infiltrating activated CD8 T cells. for immunity through a metabolic immune suppression (Fig. 3). They showed this was not correlated with elevated fatty acid Dysplasia caused by cancer cell growth and subsequent tissue oxidation of the T cells, but rather that T cells maintained a more responses including recruitment of fibroblasts and immune cells naïve phenotype [86]. In addition, macrophage and monocyte disrupts normal vascular function to restrain nutrient exchange and populations were found to change in obesity and to have reduced replenishment. This is driven in part by altered metabolism caused expression of MHC-class II that may contribute to lower T cell by oncogenic signaling in the cancer cells themselves [99], although activation in the TME [87]. the metabolic demands of inflammation and immune cells also An interesting feature of obesity-induced cancer is the duality of contribute. The complexity and heterogeneity of the TME is just increased chronic systemic inflammation but reduced local beginning to be understood and several key components contribute inflammation and T cell exhaustion in the TME. This has been to the ability to mount anti-tumor immune responses. proposed to lead to the “obesity paradox”, in which obesity is a risk factor for cancer, yet has the surprising outcome of sensitizing to Hypoxia. T cell stimulation leads to activation that results in a broad immunotherapy and improving outcomes upon immune check- increase in anabolic metabolism through aerobic glycolysis, TCA point blockade (ICB) therapy [88]. This effect is seen in multiple cycle metabolism, oxidative phosphorylation, the pentose phosphate human cancers [89–91] and recapitulated in animal models where pathway, and others [100]. This requires increased nutrient uptake, tumors grow faster with obesity, but these same tumors can including oxygen to support mitochondrial metabolism. Oxygen is respond more thoroughly to PD-1 blockade therapy [92]. T cell among the best understood nutrient sensing pathways and hypoxia dysfunction in tumors of obese animals was found to be in part is a hallmark of large or rapidly growing solid tumors. This occurs due driven by high levels of leptin that promoted PD-1 expression [92]. to insufficient vascular exchange or ineffective angiogenesis and Similarly, leptin and PD-1 ligation both increased STAT3 signaling vascular maturation that cannot match oxygen consumption within in cytotoxic T cells (CTLs) in the TME and resulted in an increase in the tumor. Tumor spaces often have regions with hypoxic oxygen CTL fatty acid oxidation and decreased glycolysis [93]. This led to tension well below 2% in areas distant to mature blood vessels pronounced CTL dysfunction as marked by a decrease in tumor whereas oxygen levels are near 5% in healthy tissues or adjacent to infiltration, cytokine and granzyme B production, and tumor vessels. Cellular responses to low oxygen tension include induction control. This study recapitulated previous findings suggesting of hypoxia-inducible factors (HIFs), most notably HIF-1α and HIF-2α, STAT3 ablation increases granzyme B and CTL proliferation [94], as that lead to transcription of hypoxia response genes and a hypoxic well as the observation that CTL dysfunction may be in part due to stress response to increase glycolysis and anerobic metabolism [101]. leptin/STAT3 signaling [89]. Leptin has also been shown to drive In T cells, HIF-1α is also activated independent of oxygen sensing in accumulation of myeloid-derived suppressor cells in the TME, response to TCR stimulation via the PI3K/mTOR pathway, TGF-B which limit CTL activation and result in increased tumor burden signaling, and IL-6 [102]. [89, 95, 96]. In addition, obesity reprograms macrophages in the Hypoxia promotes an immunosuppressive environment through TME to become pro-tumorigenic [97]. Conversely, leptin can have multiple mechanisms. Hypoxia induces expression of the ecto- directly pro-inflammatory roles in obesity and may sensitize Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. nucleotidases CD39 and CD73, increasing TME levels of the Conversely, Treg do not require high levels of glucose and can immunosuppressive nucleotide adenosine [102]. Increased expres- function without Glut1 [116]. sion of immune checkpoint molecules, including V-domain immu- While assays to measure glucose uptake and accessibility in noglobulin suppressor of T cell activation (VISTA) and cancer- tumors suggested models where glucose limitation restricts anti- associated fibroblast expression/secretion of TGF-B, IL10, VEGF, and tumor immunity, these studies have typically been performed with PD-L1 also occur under hypoxic conditions [103, 104]. Consistent bulk tumor tissue, with non-specific dye indicators [122], or at low with an immune suppressive role for a tumor hypoxic response, levels of resolution that preclude insight to which cells can capture targeting HIF-1α on tumor cells increased CTL infiltration and available glucose in the TME. This has led to a nutrient competition improved combination immunotherapy outcomes in a preclinical model in which cancer cells consume the bulk of the available mouse melanoma model [105]. Hypoxia-targeted treatment also glucose and cause a metabolic immune suppression by limiting T improved CTL infiltration and tumor control in the “immune cold” cell access to this important nutrient [114, 123]. To directly test this prostate cancer treated with ICB [106]. model, radiolabeled Positron Emission Tomography tracers were The actual role of hypoxia on CTLs, however, is complex and prior given to tumor bearing mice and tumor infiltrating cells were adaptation to hypoxic conditions can also increase T cell function in fractionated to determine which population internalized the tumors. Increased HIF activity has been shown to increase CTL labeled nutrient [113]. Interestingly, F-2DG was primarily taken invasion and function, synergizing with ICB [107] and culturing CTLs up by macrophages, followed by T cells and cancer cells while under hypoxic conditions increased their cytotoxicity in an adoptive F-glutamine was primarily taken up by cancer cells followed by cell transfer model [108]. Further supporting a hypoxic response to macrophages and T cells. Treatment with a glutamine uptake intrinsically promote T cell anti-tumor responses, T cells made inhibitor, however, increased glucose uptake in all cell populations. genetically deficient in VHL or the PHD proteins that lead to These data show that in most settings, glucose is broadly available proteolytic degradation of HIF-1α had increased anti-tumor activity in the TME and that macrophages rather than cancer cells are the [107, 109]. A potential explanation for these different observations dominant glucose consumers. Importantly, the ability of cells to involves the other signals received by CTLs in the TME vs cultured in increase glucose uptake upon inhibition of glutamine uptake hypoxia conditions in vitro. Continuous TCR stimulation in the demonstrated that glucose uptake was not widely limited by presence of hypoxia was recently shown to cause a Blimp-1 accessibility, but rather by cell intrinsic metabolic and signaling mediated repression of PGC-1α mitochondrial reprogramming, programs. eventually leadingtoanincreaseinmitochondrial ROSand dysfunctional CTLs [110]. Hypoxia, therefore, may be insufficient to Amino acids. Growing evidence has highlighted the importance of cause dysfunction in isolation, but remains an important factor in the amino acid to modulate anti-tumor responses. A wide range of complex TME. amino acids including arginine, and serine or glycine have been shown to be critical for anti-tumor effector T cell function [124] and T Glucose. Glucose is the most abundant and prototypical carbo- cell activation even in glucose replete conditions [125]. As the most hydrate fuel, but availability of this nutrient can be heterogeneous abundant amino acid, glutamine is utilized as an anabolic and in the TME. Because cancer cells themselves can use glucose at anaplerotic nutrient by cancerous cells and effector T cells [113, 126]. high rates and vascular exchange can be poor, the overall Effector T cells require glutamine uptake as genetic deletion of the availability of glucose in the interstitial space may be limited for transporter Asct2 or SNAT2 impair effector T cell responses [127– cells to uptake in the TME. While glucose remains only modestly 129]. Following uptake, glutamine is used in nucleotide or reduced and is generally available in many settings [111–113], hexosamine synthesis, transported back out of cells in exchange glucose levels in some tumor regions may be as low as 0.1 mM for other amino acids, or converted to glutamate via the enzyme [114, 115]. This heterogeneity may reflect regions with efficient glutaminase (Gls). Gls generation of glutamate then supports vascular exchange relative and other regions with necrosis and glutathione synthesis, methylation reactions, catabolism, and the high levels of death caused by insufficient nutrient access. Effector TCA cycle substrate via conversion to alpha-ketoglutarate. Despite T cells, but interestingly not Treg, require high concentrations of these widespread and important roles for glutamine, genetic or glucose and efficient glucose uptake to elicit inflammation. pharmacologic disruption of Gls had subset-specific effects on T cells Genetic deletion of the glucose transporter Slc2a1 (Glut1) can that showed that excessive glutamine uptake can be immunesup- prevent a variety of in vivo inflammatory conditions [116, 117]. pressive [130]. Th17 cells required Gls and Th17-mediated inflam- Indeed, glucose restriction in CTLs leads to decreased levels of the matory disorders were prevented by Gls inhibition. In contrast, glycolytic intermediate phosphoenolpyruvate (PEP) and decreased Th1 cells and CTLs responded to Gls inhibition by compensating Ca2+ activation of the nuclear factor for T cell activation (NFAT) through increased glucose uptake and glycolysis that increased signaling pathway to impair cytokine production [118, 119]. mTORC1 signaling, glycolysis, and production of IFNy, granzyme B, Mitochondrial dysfunction, noted by small, fragmented, hyperpo- and perforin [130]. This observed phenotype of increased activation larized mitochondria with decreased mitochondrial superoxide has since been explored by multiple groups, showing an increase in dismutase 2 (SOD2) and increased ROS, also occurs with glucose anti-tumor killing of CTLs treated with GLS inhibitors (telanglenastat, restriction [112]. Highlighting the importance of these metabolic or CB-839, and BPTES) when coupled with checkpoint immunother- disturbances, overexpressing PEP carboxykinase 1 to increase apy [131–133]. In one study, glutaminolysis inhibition resulted in a intracellular PEP levels, disrupting the PD-1/PD-L1 and CTLA-4 decrease in GSH, which in turn led to global reduction in signaling pathways, and supplementation with pyruvate can glutathionylation in the cell, including SERCA glutathionylation that increase CTL anti-tumor effector function, cytokine production, increased NF-kB signaling and PD-1 expression [131]. In addition to and mitochondrial ROS neutralization, respectively [112, 118, 119]. specific targeting of Gls, glutamine metabolism can be broadly Conversely, there may be some benefit to reduced glucose uptake inhibited using the glutamine analog 6-diazo-5-oxo-L-norleucine for anti-tumor responses. T cells that fail to differentiate to terminal (DON). DON, and a modified DON molecule to target the TME more effectors, may instead favor memory and long-lived states. This is directly due to toxicity concerns, reduced tumor burden even when potentially helpful in adoptive cell therapy or to select T cells to used as a monotherapy [134]. This approach both targets a function in low glucose environments. Consistent with this metabolic pathway preferentially used by cancer cells [113]and opportunity, activation of T cells in the glycolytic inhibitor promotes metabolic pathways favored by anti-tumor T cells 2-deoxyglucose (2DG) delayed T cell activation and effector [130, 134]. While promising, much remains to ensure T cells do function to shift nutrient use and allow greater in vivo viability not exhaust and that essential glutamine metabolic pathways are and persistence that increased anti-tumor immunity [120, 121]. not also suppressed to ultimately limit T cell persistence or function. Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. Cancer cells can also be dependent on methionine, and limiting glycolysis, and expression of functional markers such as IFNγ via methionine may bolster current therapies [135]. Indeed, methionine diminished NFAT signaling [148, 149]. In addition, the checkpoint restriction can lead to decreased tumor burden in immunocompro- molecule VISTA suppresses T cells selectively in acidic environ- mised mice to support a non-immune role for methionine in cancer ments and is upregulated in the TME [150]. While lactate can growth [135, 136]. However, activated T cells upregulate and sustain inhibit effector T cells [151], it is not just as a waste product and methionine transporters, and methionine restriction can decrease can serve as a metabolic fuel and signaling molecule. Treg are cytokine expression and increase apoptosis [137, 138]. Specifically, oxidative and can take up and consume lactate in the TME methionine depletion resulted in decreased intracellular SAM [152, 153]. Clinically, levels of lactate dehydrogenase A (LDH-A), concentrations, loss of demethylation at lysine 79 of histone H3 which converts pyruvate into lactate, correlate with worse clinical via leukemia associated methyltransferase disruptor of telomeric outcomes and fewer infiltrating T cells in multiple cancer types silencing 1-like (DOT1L), and functionally impaired CTLs [138]. [148, 154, 155]. Conversely, methionine supplementation, rather than restriction, Lactate accumulation in the TME is a rationale target for anti- may reduce tumor burden in immunocompetent systems [138]. De tumor preclinical research, yet there are complexities to the novo methionine synthesis also appears essential for maximal T cell feasibility of improving therapies via targeting this mechanism. proliferation in vivo, as a CRISPR screen of genes in the methionine While LDH-A silencing in tumor cells via shRNA failed to alter cycle of one-carbon metabolism showed a loss of T cell fitness if lactate levels, pH, or cell survival in the TME [156], a subsequent Mat2a, Mtr, or Mtrr were disrupted [139]. While further research is study utilizing nanoparticle delivery of shRNA did show a reduction needed to establish mechanistic details, our growing understanding in lactate, pH neutralization, and increased CTL infiltration and of methionine in the TME highlights the importance of studying tumor control [157]. Complicating the picture, another study found metabolic alterations in immunocompetent systems, as nutrient tumor specific LDH-A knockdown with shRNA enhanced CAR-T availability alters the survival and function of immune cells as well as treatment and reduced tumor growth, however lactate levels and cancerous ones. pH in the TME were unchanged [154]. LDH-A was also shown to Metabolism of the essential amino acid tryptophan by the play a role to regulate epigenetic marks through histone enzyme indoleamine 2,3-dioxygenase 1 (IDO1) of suppressive DCs, acetylation to promote IFN-γ expression [158]. In addition, TME TAMs, and CAFs results in both the depletion of tryptophan and neutralization has occurred in studies utilizing bicarbonate delivery accumulation of the immunosuppressive metabolite kynurenine. As and inhibition of the lactate exporter monocarboxylate transport 1 an essential amino acid, tryptophan must be obtained through the [149, 159]. One potential explanation for these discrepancies is the diet, and it cannot be replaced if it becomes limiting in tissues. IDO1 differential expression of LDH-A vs the LDH-B isoform in various is overexpressed in most cancers, and kynurenine levels in the TME tumors [156]. In addition, local lactate levels are dependent on correlate with poor prognosis in cancers such as melanoma, colon both tumor cell apoptosis and regional vascularization, which vary cancer, ovarian cancer, and AML [140–142]. Kynurenine binds to the widely between treatment conditions and tumor type. Importantly, aryl hydrocarbon receptor in naïve CD4+ T cells, promoting Treg when these lactate-targeting treatments did improve outcomes, differentiation [142]. In addition, the depletion of tryptophan in the multiple studies showed this to be a CTL-dependent effect and TME activates the stress-response kinase GCN2 in T cells, which both treatment with LDH shRNA synergized with PD-1 ICB yet failed to inhibits proliferation and induces differentiation into Tregs. GCN2 in improve tumor outcomes in immunodeficient systems [157]. DCs and TAMs also leads to expression of inhibitory cytokines such Supporting this notion, LDH inhibition controlled tumor growth as IL-10 and TGFB, leading to a suppressive milieu [143]. Given the in a preclinical humanized non-small cell lung cancer model in a role of IDO1 creating this environment, it has been the target of CD8 + T cell dependent manner [160]. It was recently shown that multiple preclinical and early clinical trials over the past few years, preconditioning CTLs with LDH-A inhibition resulted in less particularly in combination with ICB [142, 144]. While initial trial terminally differentiated CTLs upon IL-2 treatment, while treatment results were not positive, there remains a high potential for effective with IL-21 did not alter cellular metabolism but did decrease combination therapies or in specific patient subsets. transcription of LAG3, PD-1, and TIM3, leading to an overall increase in cell persistence, tumor control, and host survival [161]. Metabolites that accumulate to suppress immunity. In contrast to the depletion of anabolic nutrients in the TME, many metabolites Conclusions and perspective in addition to kynurenine can accumulate in local microenviron- In as much as it is now apparent that metabolic pathways are ments as waste or secreted products to inhibit T cells. This is intimately linked to T cell fate, it is also clear that local nutrients particularly the case in tumors or inflamed tissues where vascular and physical conditions influence these processes. While we exchange is poor. Levels of adenosine can be elevated in the TME reviewed several factors here, our understanding of these due to the release of ATP upon cell lysis which is converted to ADP processes and nutrient availability remains poor. These questions and adenosine by the ectonucleotidases CD39 and CD73 on the are challenged by the need to consider in vivo tissue hetero- surface of tumor cells. Adenosine may then act on the A2A- and geneity and the complexity of different cell types and activation A2B-receptors on T cells and APCs, respectively, to reduce CD8 T states. Nevertheless, the widespread and necessary use of cell activation, proliferation, and anti-tumor function [145]. Local biochemical and bulk tissue assays obscure cell heterogeneity accumulation of this immunosuppressive molecule impairs the in many settings. The variety of important factors for immunity in effectiveness of therapeutic approaches that induce ATP release tissues is beyond the ability to accurately model or quantitate via tumor cell lysis, prompting multiple groups efforts to disrupt using simplified in vitro. It is important, however, to focus studies conversion and adenosine signaling [145, 146]. For example, on in vivo systems and consider microenvironmental factors and utilizing a CRISPR/Cas9 approach to disrupt A2AR on CAR-T cells in tissue heterogeneity where possible. It is likewise important to culture led to an increase in IFNγ, TNFα, JAK/STAT pathway genes, consider how different cell types may interact through metabo- CAR-T cell survival, and control of tumor burden in a murine breast lites and how they may respond differently to the same nutrient cancer model [147]. pool. 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Front Oncol. 2021;11:632364. Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. 161. Hermans D, Gautam S, García-Cañaveras JC, Gromer D, Mitra S, Spolski R, et al. ADDITIONAL INFORMATION Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell Correspondence and requests for materials should be addressed to Jeffrey C. stemness and antitumor immunity. Proc Natl Acad Sci. 2020;117:6047–55. Rathmell. Reprints and permission information is available at http://www.nature.com/reprints ACKNOWLEDGEMENTS We thank members of the Rathmell lab for their input and discussions. Figures were created using BioRender. This work was supported by R01s DK105550, HL136664, AI153167, and CA217987 (JCR) and T32 GM007347 (ELF). 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Microenvironmental influences on T cell immunity in cancer and inflammation

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Abstract

www.nature.com/cmi REVIEW ARTICLE OPEN Microenvironmental influences on T cell immunity in cancer and inflammation 1,3 1,3 1,2 Darren R. Heintzman , Emilie L. Fisher and Jeffrey C. Rathmell © The Author(s), under exclusive licence to CSI and USTC 2022 T cell metabolism is dynamic and highly regulated. While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns, the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways. T cells must function in a wide variety of tissue settings, and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance. Both in inflamed and cancer tissues, a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity. These include fever and increased temperatures, depletion of critical micro and macro- nutrients, and accumulation of inhibitory waste products. Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity. Keywords: immunometabolism; T cell; microenvironment; cancer; inflammation Cellular & Molecular Immunology (2022) 19:316–326; https://doi.org/10.1038/s41423-021-00833-2 INTRODUCTION microenvironment exerts a profound influence on these processes. The classic metabolic chart present in every biology classroom and Cell activating signals, microenvironmental nutrients, and other textbook is a staple of biochemical training and represents the conditions integrate through upregulation of nutrient transporters culmination of over a century of detailed and rigorous studies. and the subsequent changes in intracellular nutrients influence cell These seminal discoveries define the landscape of fundamental bioenergetics, biosynthesis, and signaling. Metabolic signaling chemical reactions that integrate environmental signals and through generation of co-factors or posttranslational modifications nutrients to support the viability, growth, and activities of every can then serve to shape cell fate or activate metabolic checkpoints. living cell. When cells receive signals to perform specific functions These include nutrient sensing pathways such as the AMPK or such as to grow and proliferate, they adjust their nutrient uptake mTORC1 and HIF signaling axis, stress response pathways and shift metabolic programs to meet the new demands. If, including reactive oxygen species (ROS) and ER stress, or changes however, adequate levels of essential nutrients are not available or to epigenetic marks and histone modifications that regulate gene if end products or waste products accumulate, basic chemistry and expression. These changes are broadly relevant to immunity and chemical equilibriums may bring these pathways to a halt or shift inflammation and may have a particularly important impact in their outcomes to disrupt or alter cell fates. Thermodynamic effects settings such as obesity or in tumor microenvironments (TME). such as temperature changes may also influence T cells. Much the Here we review how key changes in systemic nutrient status as same as cell cycle checkpoints can stop or delay cell division, well as microenvironmental metabolites and other conditions are metabolic checkpoints thus interpret nutrients and cell energetics integrated to shape the fate of T cells. to determine cell differentiation, function, and fate. Cell metabo- lism is thus the biochemistry of how cells interpret and integrate Micronutrients and ions signals from their microenvironment. While cell metabolism typically focuses on intermediary metabo- T cells and macrophage metabolism have been studied to the lites and central carbon metabolism pathways, ions and other greatest detail in the field of immunometabolism. In addition to elements play key roles (Fig. 1A). Micronutrients such as ions have many studies focused on how cell activation signals can reprogram increasingly been shown to impact the adaptive immune system, metabolism from catabolic programs designed to generate energy particularly T cells. For example, recent literature has highlighted + + to anabolic programs that efficiently provide biosynthetic pre- that potassium (K ) can directly influence T cells. Increased K ion cursors to support cell growth and proliferation [1], it is now concentration in the tumor microenvironment can acutely silence apparent that each immune cell type and subset has specific T cell effector function [2]. In contrast, high concentrations of this metabolic requirements for activation and differentiation that ion preserve T cell stemness through acetyl CoA metabolism reflect their specific roles and demands. Importantly, the tissue and by epigenetically regulating gene transcription, nutrient 1 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37205, USA. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37205, USA. These authors contributed equally: Darren R. Heintzman, Emilie L. Fisher. email: jeff.rathmell@vumc.org Received: 15 December 2021 Accepted: 19 December 2021 Published online: 17 January 2022 1234567890();,: D.R. Heintzman et al. Fig. 1 Chemical and physical components of the tissue microenvironment that can modulate immunity. A Changes to micronutrients, including iron and potassium, regulate T cell function and survival from ferroptosis. B Increased H + and decreased pH also play important roles in T cell metabolism and fate. C Fever and high temperatures directly impact T cells to promote inflammatory states processing, and metabolism [3]. K promoted induction of incidence of disease associated with high salt intake seems to be a mitochondrial AcCoA synthetase 1, promoting mitochondrial shift in T cell differentiation toward the Th17 subset [12, 14–16]. metabolism, a metabolic feature of memory T cells. While these Th17 differentiation in high salt conditions occurs by influencing studies focused on K in the tumor microenvironment, ionic transcriptional networks during differentiation. NFAT5 and its concentrations not limited to potassium have been shown to downstream kinase SGK1 seem to be critical for an anti- produce interesting cellular phenotypes in T cells in various tissue inflammatory switch in Th17 cells [17, 18]. In contrast, high salt settings. Therefore, the ionic composition of tissues represents a has a more nuanced effect on regulatory T cells subsets. Studies relatively unexplored determinant of T cell polarization and T cell have suggested that while induced CD4( + ) Foxp3(+) regulatory effector functions. T cells are not affected in development or function by high salt H concentration is a measure of acidity in tissues and high [19], thymically derived regulatory T cells can become less concentrations of H ions may be due to hypoxic conditions and suppressive [20]. Recently, NaCl has also been suggested to be an increased abundance of cells utilizing aerobic glycolysis and an ionic checkpoint for human Th2 differentiation [21], further secreting lactate [4]. Most studies on acidity and T cell function supporting a diverse role in the differentiation and function of have been focused on the TME and how increased lactate, and T cells. While NaCl has not been well studied in terms of its effect presumably acidic conditions, in the extracellular environment on T cell metabolic programs, one may speculate that metabolic may inhibit effector T cell functions in solid tumors. A major pathways are impacted in T cells by high salt. This is highlighted by consequence of low acidity seems to be through negative effects the similarities between SGK1 and its close relative, Akt, a key on effector cytokine production by T cells, which can be severely driver of the mTORC1 pathway and T cell metabolism [22], and the reduced in acidic conditions [5–7]. Acidity is, however, not only shared activation of these kinases by mTORC2 [23]. These findings, encountered in the TME and inflammatory tissues can experience as well as future studies involving functional and metabolic pH conditions as low as ~5.5 pH [8, 9] (Fig. 1B). Interestingly, a consequences of NaCl, have implications for a wide range of recently published study shows evidence that lymph nodes also chronic inflammatory and autoimmune diseases. harbor highly acidic pH environments that suppress inflammatory Iron (Fe ) has received much attention in recent T cell literature. effector T cell functions in T cell rich zones. In this study, naïve T Iron deposition is a hallmark of many autoimmune diseases cell priming was unaffected, and T cells were able to rapidly including lupus and multiple sclerosis and plays a key role as a co- recover from acid induced inhibition within hours after pH rescue factor for many enzymes, including TCA cycle enzymes that drive [7] such as would occur upon exit from the lymph node. This mitochondrial metabolism. Excess iron, however, can also lead to provided evidence that acidic inhibition of effector functions is generation of ROS through Fenton reactions and lead to the related to changes in metabolic programming, as low pH shifted process of ferroptosis, or iron-dependent cell death. Iron uptake T cells from glycolytic metabolism to oxidative phosphorylation and handling, therefore, must be tightly regulated, and aberrant and mitochondrial metabolism. Future studies involving therapeu- iron metabolism and homeostasis have been recently shown to tic shifts in tissue pH in inflammation and disease may aid in directly influence T cell effector functions. A direct indication of the relieving chronic inflammation and other T cell mediated diseases. role of iron is shown by genetic variants of the iron uptake protein Sodium ions (Na ) also influence T cell differentiation and Transferrin Receptor, (CD71), which are associated with a common function. Peripheral tissues accumulate NaCl in high concentra- variable immune deficiency [24]. CD71 is also a highly dynamic tions in both diet-intake dependent, such as in high-salt western marker of lymphocyte activation and plasmablasts. Iron depriva- style diets, and independent mechanisms [10]. While sodium is a tion can reduce clinical scores in EAE, a T cell dependent disease in vital nutrient, excess salt is associated with higher incidence of mice [25]. Conversely, excess intracellular available iron in CD4 autoimmune diseases such as arthritis, multiple sclerosis, and in T cells was linked to the pathophysiology of SLE through a mouse studies, colitis [11–13]. One explanation for the increased mechanism of altered DNA methylation states favoring enhanced Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. immune-related gene expression [26] and by regulating the through the increased expression of alpha4 integrins and Heat stability of the RNA binding protein Pcbp1 [27]. Ferroptosis can Shock Protein 90 [44]. Other temperature-inducible proteins like play a key role to shape T cell responses. This process is redox heat shock factor-1 (HSF1) are induced at a lower temperature in T mediated and largely identified through the functions of lymphocytes than B lymphocytes (39 °C vs. 42 °C), indicating Glutathione peroxidase 4 (Gpx4), a selenoenzyme that reduces specialized functions of T cells at febrile temperatures [45, 46]. membrane phospholipid hydroperoxides to maintain cellular Several studies suggest temperature changes have significant redox homeostasis [28]. Inactivation or depletion of Gpx4 in a impacts on T cell activation, proliferation, and differentiation. In variety of cell types can induce ferroptosis [29, 30]. A recent study vitro studies suggest that T cell proliferation occurs more rapidly has shown that Tregs require Gpx4 to neutralize lipid peroxides and to a greater extent at febrile temperatures [47]. Elevated and prevent ferroptosis to maintain Treg cell activation and inhibit temperatures have also been shown to reduce costimulatory anti-tumor immunity [31]. In follicular helper T cells (Tfh), inhibition thresholds to T cell activation due to a more fluid lipid bilayer, of ferroptosis by GPX4 also protected cells from cell death in perhaps providing a mechanism to explain elevated proliferation germinal centers [32]. In tumors, CD36-mediated lipid uptake can rates [48]. Recent work has shown that T cell differentiation is also enhance ferroptosis to dampen anti-tumor immunity by promot- influenced by changes in temperature. In a report where naïve CD4 ing lipid peroxidation [33]. T cells were primed in vitro at moderate fever temperatures (39 °C), cells underwent transcriptional reprogramming which enhanced Temperature commitment toward a Th2 phenotype and away from an IFNy A physical feature of tissue microenvironments that can affect producing Th1 phenotype [49]. Interestingly, coculture with thermodynamic regulation of enzymatic rates and cell physiology dendritic cells inhibited this transcriptional transition, suggesting is temperature (Fig. 1C). Temperatures fluctuate extensively in the that cellular composition of the tissue microenvironment can human body, hovering around 37 °C in the core and central influence T cell responses at febrile temperatures. Cellular organs, such as the spleen, to as low as 28 °C in peripheral organs signaling mechanisms have been shown to be altered by changing such as the skin at thermoneutrality [34, 35]. Temperatures also temperatures in other cell types, such as recent work showing that vary widely in response to several physiological and pathophysio- NF-kB signaling is exquisitely temperature dependent in mouse logical mechanisms. Systemically, fevers can arise in many diseases adult fibroblasts and human neuroblastoma cells [50]. An and are a common side effect in bacterial and fungal infections, intriguing paper was recently published focusing on the effects blood borne cancers like lymphoma, and a variety of autoimmune of febrile temperatures on Th17 cell differentiation [51]. These and inflammatory diseases, such as Adult-Onset Stills Disease [36]. studies provided evidence that elevated temperatures predomi- While fevers are responsible for systemically increased tempera- nantly impact Th17 cell differentiation, causing this helper subset tures, localized temperature changes are also common in to enhance IL17a production. Febrile temperatures enhanced the damaged and inflamed tissue regions and have long been pathogenic gene transcription signatures of Th17 cells and caused recognized. As early as the first century B.C., observations were higher neutrophil invasion in bronchoalveolar lavage fluid in a made by Celsius that heat is a cardinal signs of inflammation [37]. mouse model of allergic airway inflammation. This study high- Over 100 years ago, studies showed that after breaking the femur lighted the potential that not only are T cells able to respond of a hamster, local temperatures at the break site rose by as many biochemically to elevated temperatures, but that this biochemical as 1–4 °C compared to non-injured limbs [38]. Interestingly, when response could have T cell-subset specific effects on immunity and ischemia was induced at the site of the break, the local inflammation. temperature rose substantially, arguing that cellular activity at A potential explanation for subset specific adaptation to the site of inflammation was responsible for increased temperature elevated temperature may be metabolic programming and and blood perfusion was necessary to dissipate this heat. These mitochondrial adaptation. Exposure of CD8( + ) T cells to febrile studies have been supported by more modern technological temperatures during activation caused significant enhancement of methodologies such as the use of temperature sensitive ratio- mitochondrial respiration in addition to enhanced extracellular metric dyes [39]. Human biology reflects these findings from mice acidification rates [52]. RNA sequencing (RNA-Seq) of CD8( + ) cells and guinea pigs and is substantiated by several publications exposed to febrile temperatures revealed that many upregulated involving rheumatoid arthritis joints. Even in remission, rheuma- gene pathways involved mitochondrial processes. Enzyme activity toid arthritis patients can exhibit elevated temperatures in increases dramatically as temperature increases, and may predict previously affected joints compared to healthy controls. In fact, increased metabolic rates in T cells at febrile temperatures due to the degree of temperature elevation in RA joints has been shown faster enzymatic reactions [53]. It has been established that Th17 to be a reliable predictive indicator of disease progression [40, 41]. cells can utilize glycolysis at a much higher rate than other T cell To date, the actual cause of locally increased temperatures at subsets[54, 55] and seem to be especially sensitive to temperature sites of inflammation is not well understood. Interestingly, change [51, 55]. Perhaps enzymatic activity involved in glycolysis is mitochondrial metabolism has been suggested to generate large enhanced at febrile temperatures. This remains a poorly under- amounts of heat through ATP hydrolysis, with mitochondria stood yet fundamental feature of inflammation. reaching temperatures close to 50 °C within cells [42]. Notably, UCP1 expression seems to correlate with mitochondrial heat Obesity generation and is highly expressed in brown fat where non- Presently over 671 million adults are classified as obese (BMI > 30 shivering thermogenesis regulates body temperature [43]. One kg/m2) and obesity contributing to a wide range of diseases with could speculate that mitochondrial metabolism conducted by underlying inflammatory components (Fig. 2), including diabetes, immune cell infiltrate in inflammation may be responsible for cardiovascular disease, and cancer [56, 57]. Research on obesity locally increased temperatures, however this has not been tested. has widely examined systemic effects of insulin resistance, but All together, these data suggest that heat generation and thermal adipose tissue of obese individuals was also found to directly characteristics within the tissue microenvironment are highly produce high levels of pro-inflammatory cytokines which influence diverse, and likely important during immune challenge. T cell and macrophage differentiation and pro-inflammatory Even with a wealth of data suggestive of frequent and variable phenotypes, including leptin, TNFα, and IL-6 [58–61]. Cell type temperature change in the tissue microenvironment, the effects of composition in obese tissues can also be dysregulated to favor temperature on immune cell function have received relatively inflammation. Obesity-associated chronic inflammation is asso- modest attention (Fig. 1C). Elevated temperatures have been ciated with an accumulation classically activated “M1” polarized shown to promote T lymphocyte trafficking during infection macrophages (ATMs) in adipose tissues [62, 63], which are highly Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. Fig. 2 Obesity leads to both systemic and local changes to T cell microenvironments. Obesity or weight loss can have striking effects on T cell metabolism in the obesity paradox in which tumors are promoted yet sensitized to anti-PD1 inflammatory and secrete pro-inflammatory cytokines like TNFα been shown to alter Treg cell metabolism and migratory function, [63]. These cells contribute to a potentially hostile environment promoting an effector-like migratory phenotype in Tregs, and which can shift the balance of immune cells toward a pro- biased migration toward sites of inflammation through a mechan- inflammatory phenotype. Trem2(+) Lipid Associated Macrophages ism of decreased mTORC1 signaling and increased fatty acid [64] are also implicated and associated with adipocyte hypertro- oxidation [72]. Recently, Tregs were shown to be critical to adipose phy, inflammation, and systemic metabolic dysregulation. While tissue homeostasis, inhibiting white adipose tissue beiging macrophages are prominent inflammatory sources in adipose through secretion of IL-10 regulated by Blimp1 expression [73]. tissue, mediators of macrophage and T cell polarization in adipose Interestingly, Treg-specific loss of IL-10 resulted in increased insulin tissue can seemingly promote either pro- or anti-inflammatory sensitivity and reduced obesity in high-fat diet-fed male mice, phenotypes and include adipokines, fatty acids, and cytokines in suggesting that Tregs may promote healthy obesity in some the tissue microenvironment. The adipokine leptin, which is settings. Together, these studies suggest that regulatory T cells secreted in proportion to adipocyte mass [65], upregulates the play a unique yet currently poorly understood role in obesity. expression of Glut1 in T cells to promote increased glucose uptake The immunological consequences of obesity have been well and glycolysis in T cells, fueling the expansion of T effector cells studied in terms of response to viral infections. In the recent like Th1 and Th17 subsets [66]. Anti-inflammatory adipokines like COVID-19 pandemic, obese individuals have been noted to be Adiponectin are also present in obese adipose tissue and have hospitalized with COVID-19 at a much higher rate than lean been shown to limit these effector cell populations by restricting individuals [74]. Similarly, obesity has been shown to impair the cell intrinsic glycolysis [67]. A constant battle thus maintains adaptive immune system in response to Influenza virus [75]. homeostasis within obese tissues, and dysregulation can cause Recent work has shown that T cells within obese tissue become meaningful swings in the outcomes of T cell differentiation and easily exhausted through upregulation of PD-1 [76], and that PD-1 function. blockade can reverses T cell priming impairments seen in obesity A key determinant of pro- or anti-inflammatory adipose [77]. While reversing PD-1 mediated exhaustion can be beneficial microenvironments is the frequency of regulatory T cells. Obese in terms of rescuing the adaptive response to viral infections, this adipose tissue seems to become a progressively hostile environ- could also increase the risk of autoimmune disorders in obese ment for regulatory T cells, as they are highly present in lean individuals. Many of the inhibitory responses in T cells due to adipose, but numbers decrease in obese adipose tissue [68]. Other obesity can be linked to T cell metabolism. Elevated saturated fatty studies have suggested that circulating regulatory T cells are also acids increase T cell antigen responses and signaling through the reduced in obesity [69]. One explanation for this is that regulatory PI3K/Akt axis to fuel fatty acid oxidation in metabolically stressed T cells can be negatively influenced by adipokines like leptin, environments [78, 79]. Obesity can also result in increased T cell which cause regulatory T cell numbers to be reduced due to the oxygen consumption and less effective response to pathogens, upregulation of glycolysis [66, 70, 71]. However, dietary lipids have and that loss of weight and return to lean state does not rescue Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. this metabolic change in T cells [80]. Activated CD4 + T cells from obese mice had increased glucose uptake and oxygen consump- tion rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose [81]. Interestingly, treatment of obese mice with metformin improved T cell responses to influenza and led to increased rates of survival. Weight loss did not, however, rescue the defects in influenza response. Why weight loss does not result in the rescue of T cell dysfunction in obesity is not well understood, but epigenetic factors associated with obesity may alter T cell chromatin dynamics, creating a seemingly irreversible metabolic shift toward higher mitochondrial respiration and worse outcomes to influenza infections. Future work in this area will be of keen interest and may identify mechanisms involved in metabolic reprogramming of T cells in obesity. Fig. 3 The tumor microenvironment and metabolic immune suppres- Obesity, cancer, and the immunotherapy obesity paradox sion. Obesity leads to chronic systemic and local inflammation. In addition to important considerations of diabetes and heart Adipose-resident CD8 T cells can be more naïve but are also sensitized disease, it is becoming increasingly clear that obesity is associated to reactivate with PD-1 blockade. Many factors contribute to this with cancer incidence and mortality. In this section we will focus obesity paradox, including elevated lactate, decreased glucose, and on how these factors alter the local TME (Fig. 2). The pro- altered amino acids tumorigenic mechanisms behind obesity are multifactorial and include direct effects of systemic hormones and nutrients on the macrophages with increased potential to drive inflammation [98]. cancer cells [82]. Chronic inflammation, long-chain fatty acid Consistent with a pro-inflammatory role for leptin, treatment of metabolism, and consumption of high fructose corn syrup have all lean mice with leptin was sufficient to increase anti-tumor been implicated to directly promote tumorigenesis, independent immunity to an extent similar to PD-1 blockade [87]. Clearly, of their alterations to the anti-tumor immune response [83–85]. obesity and hormones such as leptin play complex roles in the This adds complexity in elucidating the mechanisms involved in TME. Given the prevalence of obesity and the potential for new altering the tumor vs immune system balance and may help insight from obesity that may improve immunotherapy in lean explain differences observed by groups in the field. Single cell individuals, however, makes this an exciting and important area for RNA-Seq studies of changes to immune cell populations in tumors further discovery. of lean and obese mice have shown a variety of potentially impactful changes [86, 87]. Ringel et al. showed that obesity led to The tumor microenvironment increased tumor growth that was particularly apparent in TMEs are heterogeneous and composed of mixed cell types, immunocompetent mice and that tumors from obese mice had nutrients, and stroma that can present a metabolically hostile setting decreased abundance of tumor infiltrating activated CD8 T cells. for immunity through a metabolic immune suppression (Fig. 3). They showed this was not correlated with elevated fatty acid Dysplasia caused by cancer cell growth and subsequent tissue oxidation of the T cells, but rather that T cells maintained a more responses including recruitment of fibroblasts and immune cells naïve phenotype [86]. In addition, macrophage and monocyte disrupts normal vascular function to restrain nutrient exchange and populations were found to change in obesity and to have reduced replenishment. This is driven in part by altered metabolism caused expression of MHC-class II that may contribute to lower T cell by oncogenic signaling in the cancer cells themselves [99], although activation in the TME [87]. the metabolic demands of inflammation and immune cells also An interesting feature of obesity-induced cancer is the duality of contribute. The complexity and heterogeneity of the TME is just increased chronic systemic inflammation but reduced local beginning to be understood and several key components contribute inflammation and T cell exhaustion in the TME. This has been to the ability to mount anti-tumor immune responses. proposed to lead to the “obesity paradox”, in which obesity is a risk factor for cancer, yet has the surprising outcome of sensitizing to Hypoxia. T cell stimulation leads to activation that results in a broad immunotherapy and improving outcomes upon immune check- increase in anabolic metabolism through aerobic glycolysis, TCA point blockade (ICB) therapy [88]. This effect is seen in multiple cycle metabolism, oxidative phosphorylation, the pentose phosphate human cancers [89–91] and recapitulated in animal models where pathway, and others [100]. This requires increased nutrient uptake, tumors grow faster with obesity, but these same tumors can including oxygen to support mitochondrial metabolism. Oxygen is respond more thoroughly to PD-1 blockade therapy [92]. T cell among the best understood nutrient sensing pathways and hypoxia dysfunction in tumors of obese animals was found to be in part is a hallmark of large or rapidly growing solid tumors. This occurs due driven by high levels of leptin that promoted PD-1 expression [92]. to insufficient vascular exchange or ineffective angiogenesis and Similarly, leptin and PD-1 ligation both increased STAT3 signaling vascular maturation that cannot match oxygen consumption within in cytotoxic T cells (CTLs) in the TME and resulted in an increase in the tumor. Tumor spaces often have regions with hypoxic oxygen CTL fatty acid oxidation and decreased glycolysis [93]. This led to tension well below 2% in areas distant to mature blood vessels pronounced CTL dysfunction as marked by a decrease in tumor whereas oxygen levels are near 5% in healthy tissues or adjacent to infiltration, cytokine and granzyme B production, and tumor vessels. Cellular responses to low oxygen tension include induction control. This study recapitulated previous findings suggesting of hypoxia-inducible factors (HIFs), most notably HIF-1α and HIF-2α, STAT3 ablation increases granzyme B and CTL proliferation [94], as that lead to transcription of hypoxia response genes and a hypoxic well as the observation that CTL dysfunction may be in part due to stress response to increase glycolysis and anerobic metabolism [101]. leptin/STAT3 signaling [89]. Leptin has also been shown to drive In T cells, HIF-1α is also activated independent of oxygen sensing in accumulation of myeloid-derived suppressor cells in the TME, response to TCR stimulation via the PI3K/mTOR pathway, TGF-B which limit CTL activation and result in increased tumor burden signaling, and IL-6 [102]. [89, 95, 96]. In addition, obesity reprograms macrophages in the Hypoxia promotes an immunosuppressive environment through TME to become pro-tumorigenic [97]. Conversely, leptin can have multiple mechanisms. Hypoxia induces expression of the ecto- directly pro-inflammatory roles in obesity and may sensitize Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. nucleotidases CD39 and CD73, increasing TME levels of the Conversely, Treg do not require high levels of glucose and can immunosuppressive nucleotide adenosine [102]. Increased expres- function without Glut1 [116]. sion of immune checkpoint molecules, including V-domain immu- While assays to measure glucose uptake and accessibility in noglobulin suppressor of T cell activation (VISTA) and cancer- tumors suggested models where glucose limitation restricts anti- associated fibroblast expression/secretion of TGF-B, IL10, VEGF, and tumor immunity, these studies have typically been performed with PD-L1 also occur under hypoxic conditions [103, 104]. Consistent bulk tumor tissue, with non-specific dye indicators [122], or at low with an immune suppressive role for a tumor hypoxic response, levels of resolution that preclude insight to which cells can capture targeting HIF-1α on tumor cells increased CTL infiltration and available glucose in the TME. This has led to a nutrient competition improved combination immunotherapy outcomes in a preclinical model in which cancer cells consume the bulk of the available mouse melanoma model [105]. Hypoxia-targeted treatment also glucose and cause a metabolic immune suppression by limiting T improved CTL infiltration and tumor control in the “immune cold” cell access to this important nutrient [114, 123]. To directly test this prostate cancer treated with ICB [106]. model, radiolabeled Positron Emission Tomography tracers were The actual role of hypoxia on CTLs, however, is complex and prior given to tumor bearing mice and tumor infiltrating cells were adaptation to hypoxic conditions can also increase T cell function in fractionated to determine which population internalized the tumors. Increased HIF activity has been shown to increase CTL labeled nutrient [113]. Interestingly, F-2DG was primarily taken invasion and function, synergizing with ICB [107] and culturing CTLs up by macrophages, followed by T cells and cancer cells while under hypoxic conditions increased their cytotoxicity in an adoptive F-glutamine was primarily taken up by cancer cells followed by cell transfer model [108]. Further supporting a hypoxic response to macrophages and T cells. Treatment with a glutamine uptake intrinsically promote T cell anti-tumor responses, T cells made inhibitor, however, increased glucose uptake in all cell populations. genetically deficient in VHL or the PHD proteins that lead to These data show that in most settings, glucose is broadly available proteolytic degradation of HIF-1α had increased anti-tumor activity in the TME and that macrophages rather than cancer cells are the [107, 109]. A potential explanation for these different observations dominant glucose consumers. Importantly, the ability of cells to involves the other signals received by CTLs in the TME vs cultured in increase glucose uptake upon inhibition of glutamine uptake hypoxia conditions in vitro. Continuous TCR stimulation in the demonstrated that glucose uptake was not widely limited by presence of hypoxia was recently shown to cause a Blimp-1 accessibility, but rather by cell intrinsic metabolic and signaling mediated repression of PGC-1α mitochondrial reprogramming, programs. eventually leadingtoanincreaseinmitochondrial ROSand dysfunctional CTLs [110]. Hypoxia, therefore, may be insufficient to Amino acids. Growing evidence has highlighted the importance of cause dysfunction in isolation, but remains an important factor in the amino acid to modulate anti-tumor responses. A wide range of complex TME. amino acids including arginine, and serine or glycine have been shown to be critical for anti-tumor effector T cell function [124] and T Glucose. Glucose is the most abundant and prototypical carbo- cell activation even in glucose replete conditions [125]. As the most hydrate fuel, but availability of this nutrient can be heterogeneous abundant amino acid, glutamine is utilized as an anabolic and in the TME. Because cancer cells themselves can use glucose at anaplerotic nutrient by cancerous cells and effector T cells [113, 126]. high rates and vascular exchange can be poor, the overall Effector T cells require glutamine uptake as genetic deletion of the availability of glucose in the interstitial space may be limited for transporter Asct2 or SNAT2 impair effector T cell responses [127– cells to uptake in the TME. While glucose remains only modestly 129]. Following uptake, glutamine is used in nucleotide or reduced and is generally available in many settings [111–113], hexosamine synthesis, transported back out of cells in exchange glucose levels in some tumor regions may be as low as 0.1 mM for other amino acids, or converted to glutamate via the enzyme [114, 115]. This heterogeneity may reflect regions with efficient glutaminase (Gls). Gls generation of glutamate then supports vascular exchange relative and other regions with necrosis and glutathione synthesis, methylation reactions, catabolism, and the high levels of death caused by insufficient nutrient access. Effector TCA cycle substrate via conversion to alpha-ketoglutarate. Despite T cells, but interestingly not Treg, require high concentrations of these widespread and important roles for glutamine, genetic or glucose and efficient glucose uptake to elicit inflammation. pharmacologic disruption of Gls had subset-specific effects on T cells Genetic deletion of the glucose transporter Slc2a1 (Glut1) can that showed that excessive glutamine uptake can be immunesup- prevent a variety of in vivo inflammatory conditions [116, 117]. pressive [130]. Th17 cells required Gls and Th17-mediated inflam- Indeed, glucose restriction in CTLs leads to decreased levels of the matory disorders were prevented by Gls inhibition. In contrast, glycolytic intermediate phosphoenolpyruvate (PEP) and decreased Th1 cells and CTLs responded to Gls inhibition by compensating Ca2+ activation of the nuclear factor for T cell activation (NFAT) through increased glucose uptake and glycolysis that increased signaling pathway to impair cytokine production [118, 119]. mTORC1 signaling, glycolysis, and production of IFNy, granzyme B, Mitochondrial dysfunction, noted by small, fragmented, hyperpo- and perforin [130]. This observed phenotype of increased activation larized mitochondria with decreased mitochondrial superoxide has since been explored by multiple groups, showing an increase in dismutase 2 (SOD2) and increased ROS, also occurs with glucose anti-tumor killing of CTLs treated with GLS inhibitors (telanglenastat, restriction [112]. Highlighting the importance of these metabolic or CB-839, and BPTES) when coupled with checkpoint immunother- disturbances, overexpressing PEP carboxykinase 1 to increase apy [131–133]. In one study, glutaminolysis inhibition resulted in a intracellular PEP levels, disrupting the PD-1/PD-L1 and CTLA-4 decrease in GSH, which in turn led to global reduction in signaling pathways, and supplementation with pyruvate can glutathionylation in the cell, including SERCA glutathionylation that increase CTL anti-tumor effector function, cytokine production, increased NF-kB signaling and PD-1 expression [131]. In addition to and mitochondrial ROS neutralization, respectively [112, 118, 119]. specific targeting of Gls, glutamine metabolism can be broadly Conversely, there may be some benefit to reduced glucose uptake inhibited using the glutamine analog 6-diazo-5-oxo-L-norleucine for anti-tumor responses. T cells that fail to differentiate to terminal (DON). DON, and a modified DON molecule to target the TME more effectors, may instead favor memory and long-lived states. This is directly due to toxicity concerns, reduced tumor burden even when potentially helpful in adoptive cell therapy or to select T cells to used as a monotherapy [134]. This approach both targets a function in low glucose environments. Consistent with this metabolic pathway preferentially used by cancer cells [113]and opportunity, activation of T cells in the glycolytic inhibitor promotes metabolic pathways favored by anti-tumor T cells 2-deoxyglucose (2DG) delayed T cell activation and effector [130, 134]. While promising, much remains to ensure T cells do function to shift nutrient use and allow greater in vivo viability not exhaust and that essential glutamine metabolic pathways are and persistence that increased anti-tumor immunity [120, 121]. not also suppressed to ultimately limit T cell persistence or function. Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. Cancer cells can also be dependent on methionine, and limiting glycolysis, and expression of functional markers such as IFNγ via methionine may bolster current therapies [135]. Indeed, methionine diminished NFAT signaling [148, 149]. In addition, the checkpoint restriction can lead to decreased tumor burden in immunocompro- molecule VISTA suppresses T cells selectively in acidic environ- mised mice to support a non-immune role for methionine in cancer ments and is upregulated in the TME [150]. While lactate can growth [135, 136]. However, activated T cells upregulate and sustain inhibit effector T cells [151], it is not just as a waste product and methionine transporters, and methionine restriction can decrease can serve as a metabolic fuel and signaling molecule. Treg are cytokine expression and increase apoptosis [137, 138]. Specifically, oxidative and can take up and consume lactate in the TME methionine depletion resulted in decreased intracellular SAM [152, 153]. Clinically, levels of lactate dehydrogenase A (LDH-A), concentrations, loss of demethylation at lysine 79 of histone H3 which converts pyruvate into lactate, correlate with worse clinical via leukemia associated methyltransferase disruptor of telomeric outcomes and fewer infiltrating T cells in multiple cancer types silencing 1-like (DOT1L), and functionally impaired CTLs [138]. [148, 154, 155]. Conversely, methionine supplementation, rather than restriction, Lactate accumulation in the TME is a rationale target for anti- may reduce tumor burden in immunocompetent systems [138]. De tumor preclinical research, yet there are complexities to the novo methionine synthesis also appears essential for maximal T cell feasibility of improving therapies via targeting this mechanism. proliferation in vivo, as a CRISPR screen of genes in the methionine While LDH-A silencing in tumor cells via shRNA failed to alter cycle of one-carbon metabolism showed a loss of T cell fitness if lactate levels, pH, or cell survival in the TME [156], a subsequent Mat2a, Mtr, or Mtrr were disrupted [139]. While further research is study utilizing nanoparticle delivery of shRNA did show a reduction needed to establish mechanistic details, our growing understanding in lactate, pH neutralization, and increased CTL infiltration and of methionine in the TME highlights the importance of studying tumor control [157]. Complicating the picture, another study found metabolic alterations in immunocompetent systems, as nutrient tumor specific LDH-A knockdown with shRNA enhanced CAR-T availability alters the survival and function of immune cells as well as treatment and reduced tumor growth, however lactate levels and cancerous ones. pH in the TME were unchanged [154]. LDH-A was also shown to Metabolism of the essential amino acid tryptophan by the play a role to regulate epigenetic marks through histone enzyme indoleamine 2,3-dioxygenase 1 (IDO1) of suppressive DCs, acetylation to promote IFN-γ expression [158]. In addition, TME TAMs, and CAFs results in both the depletion of tryptophan and neutralization has occurred in studies utilizing bicarbonate delivery accumulation of the immunosuppressive metabolite kynurenine. As and inhibition of the lactate exporter monocarboxylate transport 1 an essential amino acid, tryptophan must be obtained through the [149, 159]. One potential explanation for these discrepancies is the diet, and it cannot be replaced if it becomes limiting in tissues. IDO1 differential expression of LDH-A vs the LDH-B isoform in various is overexpressed in most cancers, and kynurenine levels in the TME tumors [156]. In addition, local lactate levels are dependent on correlate with poor prognosis in cancers such as melanoma, colon both tumor cell apoptosis and regional vascularization, which vary cancer, ovarian cancer, and AML [140–142]. Kynurenine binds to the widely between treatment conditions and tumor type. Importantly, aryl hydrocarbon receptor in naïve CD4+ T cells, promoting Treg when these lactate-targeting treatments did improve outcomes, differentiation [142]. In addition, the depletion of tryptophan in the multiple studies showed this to be a CTL-dependent effect and TME activates the stress-response kinase GCN2 in T cells, which both treatment with LDH shRNA synergized with PD-1 ICB yet failed to inhibits proliferation and induces differentiation into Tregs. GCN2 in improve tumor outcomes in immunodeficient systems [157]. DCs and TAMs also leads to expression of inhibitory cytokines such Supporting this notion, LDH inhibition controlled tumor growth as IL-10 and TGFB, leading to a suppressive milieu [143]. Given the in a preclinical humanized non-small cell lung cancer model in a role of IDO1 creating this environment, it has been the target of CD8 + T cell dependent manner [160]. It was recently shown that multiple preclinical and early clinical trials over the past few years, preconditioning CTLs with LDH-A inhibition resulted in less particularly in combination with ICB [142, 144]. While initial trial terminally differentiated CTLs upon IL-2 treatment, while treatment results were not positive, there remains a high potential for effective with IL-21 did not alter cellular metabolism but did decrease combination therapies or in specific patient subsets. transcription of LAG3, PD-1, and TIM3, leading to an overall increase in cell persistence, tumor control, and host survival [161]. Metabolites that accumulate to suppress immunity. In contrast to the depletion of anabolic nutrients in the TME, many metabolites Conclusions and perspective in addition to kynurenine can accumulate in local microenviron- In as much as it is now apparent that metabolic pathways are ments as waste or secreted products to inhibit T cells. This is intimately linked to T cell fate, it is also clear that local nutrients particularly the case in tumors or inflamed tissues where vascular and physical conditions influence these processes. While we exchange is poor. Levels of adenosine can be elevated in the TME reviewed several factors here, our understanding of these due to the release of ATP upon cell lysis which is converted to ADP processes and nutrient availability remains poor. These questions and adenosine by the ectonucleotidases CD39 and CD73 on the are challenged by the need to consider in vivo tissue hetero- surface of tumor cells. Adenosine may then act on the A2A- and geneity and the complexity of different cell types and activation A2B-receptors on T cells and APCs, respectively, to reduce CD8 T states. Nevertheless, the widespread and necessary use of cell activation, proliferation, and anti-tumor function [145]. Local biochemical and bulk tissue assays obscure cell heterogeneity accumulation of this immunosuppressive molecule impairs the in many settings. The variety of important factors for immunity in effectiveness of therapeutic approaches that induce ATP release tissues is beyond the ability to accurately model or quantitate via tumor cell lysis, prompting multiple groups efforts to disrupt using simplified in vitro. It is important, however, to focus studies conversion and adenosine signaling [145, 146]. For example, on in vivo systems and consider microenvironmental factors and utilizing a CRISPR/Cas9 approach to disrupt A2AR on CAR-T cells in tissue heterogeneity where possible. It is likewise important to culture led to an increase in IFNγ, TNFα, JAK/STAT pathway genes, consider how different cell types may interact through metabo- CAR-T cell survival, and control of tumor burden in a murine breast lites and how they may respond differently to the same nutrient cancer model [147]. pool. 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Front Oncol. 2021;11:632364. Cellular & Molecular Immunology (2022) 19:316 – 326 D.R. Heintzman et al. 161. Hermans D, Gautam S, García-Cañaveras JC, Gromer D, Mitra S, Spolski R, et al. ADDITIONAL INFORMATION Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell Correspondence and requests for materials should be addressed to Jeffrey C. stemness and antitumor immunity. Proc Natl Acad Sci. 2020;117:6047–55. Rathmell. Reprints and permission information is available at http://www.nature.com/reprints ACKNOWLEDGEMENTS We thank members of the Rathmell lab for their input and discussions. Figures were created using BioRender. This work was supported by R01s DK105550, HL136664, AI153167, and CA217987 (JCR) and T32 GM007347 (ELF). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give AUTHOR CONTRIBUTIONS appropriate credit to the original author(s) and the source, provide a link to the Creative All authors contributed equally to the research, drafting, and editing of this Commons license, and indicate if changes were made. The images or other third party manuscript. material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory COMPETING INTERESTS regulation or exceeds the permitted use, you will need to obtain permission directly JCR is a founder, scientific advisory board member, and stockholder of Sitryx from the copyright holder. To view a copy of this license, visit http://creativecommons. Therapeutics, a scientific advisory board member and stockholder of Caribou org/licenses/by/4.0/. Biosciences, a member of the scientific advisory board of Nirogy Therapeutics, has consulted for Merck, Pfizer, and Mitobridge within the past 3 years, and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. © The Author(s), under exclusive licence to CSI and USTC 2022 Cellular & Molecular Immunology (2022) 19:316 – 326

Journal

Cellular and Molecular ImmunologySpringer Journals

Published: Mar 1, 2022

Keywords: immunometabolism; T cell; microenvironment; cancer; inflammation

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