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Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors

Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors Hindawi Journal of Oncology Volume 2019, Article ID 7317964, 11 pages https://doi.org/10.1155/2019/7317964 Review Article Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors 1 1 2 3 Giuseppe Schepisi , Nicole Brighi, Maria Concetta Cursano, Giorgia Gurioli, 4 1 1 4 1 GiorgiaRavaglia, AmeliaAltavilla, SalvatoreLucaBurgio, SaraTestoni, CeciliaMenna, 1 1 2 2 1 Alberto Farolfi, Chiara Casadei, Giuseppe Tonini, Daniele Santini, and Ugo De Giorgi Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Medical Oncology Department, Campus Bio-Medico University, Rome, Italy Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Correspondence should be addressed to Giuseppe Schepisi; giuseppe.schepisi@irst.emr.it Received 7 May 2019; Revised 28 August 2019; Accepted 6 September 2019; Published 19 September 2019 Guest Editor: Xuelei Ma Copyright © 2019 Giuseppe Schepisi et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secondary resistance to immunotherapy: tumor-derived protein and cytokines, tumor mutational burden, and patient performance status and comorbidities can condition tumor re- sponse to ICIs. Recently, some of these factors have been evaluated as potential biomarkers of response, with conflicting results. To date, the expression of programmed death-ligand 1 (PD-L1) and the presence of deficient mismatch repair (dMMR) in tumor tissue are the only biomarkers capable of guiding the clinician’s decision in urothelial cancer and prostate cancer, respectively. In this review, we performed a comprehensive search of the main publications on biomarkers that are predictive of response to ICIs in urological cancers. Our aim was to understand whether existing data have the potential to drive clinical decision-making in the near future. persists. According to the tumor immunity in the microen- 1. Introduction vironment (TIME) classification [1], tumors can be divided Immunotherapy is fast becoming the new frontier of on- into 4 subgroups based on the presence of inflammatory − − cology, accompanied by the dream of being able to defeat infiltrate (TIL) and PD-L1 expression: T1 (PD-L1 , TIL ), T2 + + − + + − cancer definitively. Although a substantial improvement in (PD-L1 , TIL ), T3 (PD-L1 , TIL ), and T4 (PD-L1 , TIL ) survival has been seen since immunotherapy was first used in (Figure 1). Although the TIME classification has significant melanoma, response remains low. (e use of different types of predictive implications, there is an increasing need to find immune-checkpoint inhibitors (ICIs), in particular the pro- predictive markers of response to ICIs. grammed death-1/programmed death-ligand 1 (PD-1/PD- L1) axis, has led to significantly better results in terms of 2. Factors Involved in Primary and Secondary response and manageability. In recent years, advances have Resistance to ICIs in Solid Tumors been made in the treatment of urological tumors, especially renal cell cancer (RCC) and urothelial cancer (UC). However, Several factors can directly or indirectly influence the im- the issue of the identification of nonresponding patients mune response and therefore contribute to triggering 2 Journal of Oncology Tumor cell – – + + T1: PD-L1 TIL T2: PD-L1 TIL Tumor-infiltrating – + + – lymphocyte (TIL) T3: PD-L1 TIL T4: PD-L1 TIL Programmed death-ligand 1 (PD-L1) Figure 1: Four tumor subtypes according to the TIME classification based on the expression of PD-L1 in tumor cells and on the presence of TILs. resistance mechanisms. As shown in Figure 2, these factors markers capable of activating the immune response. Con- can be divided into two categories: versely, a high expression of mutations, i.e., tumor muta- tional burden (TMB), especially if mismatch repair genes are (1) Patient-related factors: it is acknowledged that pa- involved, correlates with a high RR to ICIs, regardless of tients in poor clinical conditions have a lower immune histology [20–23]. In UC, a recent study showed a higher RR response. However, the underlying mechanism for in patients with alterations in the following genes: ATM, this is still not understood. In fact, Pan et al. reported BRCA2, ERCC2, FANCA, MSH6, and POLE [24]. However, that an Eastern Cooperative Oncology Group per- unlike solid tumors, elevated TMB has been associated with formance score (ECOG PS) of 2 in melanoma patients poor prognosis in hematological cancers, for example, was associated with worse prognosis when ICIs were multiple myeloma [25]. (e growing interest in TMB has led used [2]. Conversely, a study carried out on patients to the development of studies aimed at testing the efficacy of with UC treated with atezolizumab showed that re- neoantigens, structured within new molecules, such as sponse rates (RRs) did not differ among patients with chimeric antigen T-cell receptor therapy (CAR-T). Several different PS [3]. Recently, several trials conducted on studies are also underway for patients with RCC [26–28] and UC demonstrated a shorter overall survival (OS) in prostate tumors (PCa) [29]. patients with ECOG PS> 2 compared with ECOG PS PD-L1 expression in tumor tissue is one of the best 0 [3–6]. Several comorbidities can also affect the known mechanisms for neutralizing immune system ac- immune response: autoimmune diseases [7, 8], di- tivity. A higher PD-L1 expression results in a poorer abetes [9], transplantations [10–12] (including bone prognosis without the use of ICIs [13]. However, PD-L1 is marrow transplants), and infections [13]. Another not always capable of predicting response to ICIs [30, 31]. In important host-related factor is gut microbiota: sev- fact, although response rates in UC differ significantly on the eral studies have shown that restoration of some basis of PD-L1 status, this is not the case for RCC patients bacterial families (Ruminococcaceae [14], Akker- [32, 33]. mansia muciniphila [15], and Bacteroides fragilis [16]) To date, CTLA-4 and PD1/PD-L1 axis are not the only is correlated with a longer response in melanoma mice molecules involved in the modulation of the immune re- treated with anti-PD1 drugs. (us, the use of anti- sponse. Other molecules are currently under investigation as biotics or steroids during ICI therapy may affect the potential immune checkpoint for new ICIs, e.g., lymphocyte- outcome of treatment. In particular, 2 recent studies activation gene-3 (LAG-3), T-cell immunoglobulin mucin-3 [17, 18] showed that the use of beta-lactams, quino- (TIM-3), and B7-H3 and B7-H4/B7x/B7S1. lones, and macrolides during ICIs therapy also led to LAG-3 molecule is located on the cell surface of several shorter progression-free survival (PFS) and poorer RR immune cells; its ligand is Class II MHC and binds with in RCC patients. higher affinity than CD4 [34]. LAG-3 downregulates the + + (2) Tumor-related factors: this category can be divided immune response of CD4 - and CD8 -activated cells. In into 2 subcategories: intratumoral and microenvi- fact, its negative activity has been observed in CD8 tumor- ronmental factors. infiltrating lymphocytes (TILs) and in CD4 TRegs [35]. TIM-3 is a regulatory molecule expressed on the surface of innate immune cells; CD8 TILs usually coexpress PD-L1 2.1. Intratumoral Factors. Among tumor-related factors, and TIM-3, causing a strong inhibition of cytokine secretion [36]. To date, TIM-3/PD-L1 coexpression has also been different histologies and the presence of chromosomal al- terations influence the immune response. For example, studied in CD8 cells in melanoma patients. In one study, blocking both PD-L1 and TIM-3 led to a restoration of strongly aneuploid tumors have shown an intrinsic re- sistance to ICIs [19]. (is is due to the poor expression of cytokine secretion [37]. Journal of Oncology 3 Performance Comorbidities Status Tumor-related Intratumoral Microenviromental (i) Histology (i) TILs (ii) Chromosome alterations (ii) IDO (iii) TMB (iii) TGF-β (iv) PD-L1 (iv) CXCR3 ligands (CXCL9-CXCL10) (v) LAG-3 (v) NLR Gut microbiota (vi) TIM-3 (vi) SII (vii) B7-H3, B7-H4 Patient-related Figure 2: Factors influencing immune response and possibly related to resistance to immunotherapy. TMB: tumor mutational burden; PD- L1: programmed death-ligand 1; LAG-3: lymphocyte-activation gene-3; TIM-3: T-cell immunoglobulin and mucin domain 3; TILs: tumor- infiltrating lymphocytes; IDO: indoleamine-2,3-dioxygenase; TGF-β: transforming growth factor-β; CXCR: CXC chemokine receptors; CXCL: CXC chemokine receptors ligands; NLR: neutrophil-to-lymphocyte ratio; SII: systemic immune-inflammation index. B7-H3 and B7-H4 (also known as B7x/B7S1) are 2 anti-CTLA4 antibodies or CAR-T-cell therapy. However, members of the B7 super-family expressed not only by some negative PD-L1 tumors may respond to an anti-PD-L1 immune cells but also by nonlymphoid tissues, including drug. Positivity or negativity of the histological examination prostate and testis cells [38]. Although B7-H3 was initially may not reflect a common characteristic of the overall tumor. characterized as a costimulatory molecule, recent studies (us, tumor heterogeneity may be responsible for ICI re- have indicated its dual activity. In some cases, it acts as an sponse in patients with PD-L1-negative biopsy [1]. It is also a upregulator of the immune responses and in others, a unstable characteristic over time; in fact, treatment may select downregulator [39]. altered tumor cells capable of activating the process of im- mune escape, blocking the immune system activation, and even transforming positive TIL into negative TIL tumors. (is 2.2. Microenvironmental Factors. Tumor microenvironment condition has been described in different tumor types, such as plays an important role in silencing the immune response. lung and breast cancer and RCC [46–48]. In particular, Usually, the presence of TILs is related to higher PD-L1 discordance in PD-L1 status between primary and metastatic expression [40, 41] and to better response to ICI treatment sites has been observed in 20% of RCC patients [49]. (e [23]. (e KEYNOTE 028 study tested the efficacy of pem- immune-silencing process is ascribed to several mechanisms: brolizumab in 20 different tumors. Results showed that activation of the Wnt–β-catenin pathway [50]; loss of PTEN treatment with ICIs was more effective in patients with TILs, associated with AKT activation [51]; and loss of immuno- independently of tumor histology [42]. genicity [52] through several mechanisms (including On the other hand, the aforementioned TIME classifi- downregulation of MHC class I molecules and reduced cation [1] has emphasized the link between TILs and PD-L1 in production of immunogenic antigens). determining the response to ICIs. However, its correlation (e study of the tumor microenvironment has led to the with response in UTs is still under evaluation [43]. (e T2 discovery of other molecules involved in immune-silencing subgroup, for example, is characterized by the presence of mechanisms. For example, indoleamine-2,3-dioxygenase TILs and higher PD-L1 expression, stimulated by the TIL- (IDO) is a molecule produced in TILs capable of stimulating mediated production of interferon-gamma (IFN-c). (is the immune infiltrate, reducing the concentration of tryp- subgroup is associated with high RRs when treated with ICIs. tophan which is necessary for the activation of cytotoxic Unlike T2, the T3 subgroup expresses TILs but not PD-L1 T cells, and permitting their transformation into regulatory (probably due to a nonexpression of inducing factors, such as T cells (TRegs). (is promotes an immunosuppressive mi- IFN-c). In this context, the use of OX-40 or 4-1BB agonists croenvironment near the tumor. Consequently, IDO is a may convert tumors classified as T3 into T2 [44, 45]. T1 and promising biomarker, and high concentrations are associ- T4 subgroups differ because of their lack of TILs. Many ated with worse prognosis. However, IDO as a target for new tumors have this characteristic, which is usually associated drug development has been disappointing, and the use of with a nonresponse to treatment with ICIs. (ere are different ways to stimulate the immune response, for example, by using IDO inhibitors has not shown any advantages over ICI 4 Journal of Oncology treatment [53]. In addition to IDO, there is a high expression activity and acceptable tolerability in the first-line treatment of other molecules in tumor microenvironment, including of cisplatin-ineligible patients [3, 5]. Based on these results, the Food and Drug Administration (FDA) approved ate- TGF-β secreted by fibroblasts [54], and various other cy- tokines involved in immune-silencing mechanisms. Among zolizumab and pembrolizumab in this subgroup. However, these molecules, CXCL9 and CXCL10, two CXCR3 ligands, the FDA updated the prescribing information for first-line have shown to be correlated with the TIL-positive TIME pembrolizumab and atezolizumab in cisplatin-ineligible subgroups, whereas TIL-negative subgroups lack these patients, making it compulsory to use an approved PD-L1 chemokines [55, 56]. diagnostic test (Dako PDL-1 ICH 22C PharmDx Assay Furthermore, several studies have evaluated the prog- and Ventana PDL-1 Assay ) to select patients. (erefore, nostic/predictive role of some parameters, such as the FDA indications were modified as follows: cisplatin-unfit neutrophil-to-lymphocyte ratio (NLR) and the systemic patients are eligible for pembrolizumab and atezolizumab if immune-inflammation index (SII). NLR is the most widely the tumor expresses PD-L1 (CPS≥ 10 for pembrolizumab tested prognostic index and correlates with prognosis in and PD-L1≥ 5% for atezolizumab) [70]. In patients not different tumor types [57]. Similarly, SII, combining eligible for any platinum, pembrolizumab and atezolizumab neutrophils, lymphocytes, and platelet count in a single can be administered in first-line regardless of tumor PD-L1 parameter, demonstrates a significant correlation with expression. In postplatinum UC patients, several trials have prognosis in different cancers [58–60]. Among UTs, SII and demonstrated ICI efficacy [71–75], with ICI-treated PD-L1- NLR have shown a prognostic and predictive role of re- positive TIL-positive UCs showing higher RRs. In the sponse to conventional treatment in several retrospective IMvigor 210 trial, the use of atezolizumab obtained an trials [61–63]. In particular, Lalani et al. recently demon- overall response rate (ORR) of 16%, which was higher (28%) strated that an early reduction in NLR (at 6 weeks) was in patients with ≥5% PD-L1 expression [71]. In CheckMate associated with a significantly improved outcome in mRCC 275, patients with tumor cluster III proved most likely to patients after ICI treatment [64]. Moreover, Raccioppi et al. obtain a better response to nivolumab (30%) [73]. Similar found that preoperatory NLR value was a predictor of re- results were obtained in 2 other studies. In the JAVELIN sponse to BCG therapy in non-muscle-invasive bladder trial, avelumab demonstrated an ORR of 17% in all patients cancer [65]. and 50% in those showing PD-L1 expression [75]. In a phase 1/2 trial, durvalumab obtained an ORR of 31% in the overall population, 46% in patients with PD-L1 expression, and 0% 3. Potential Prognostic and Predictive in those without PD-L1 expression [76]. Based on these Biomarkers in UCs Treated with ICIs results, the FDA approved pembrolizumab as the preferred 3.1. PD-L1 and TILs. PD-L1 is the most widely studied drug, with atezolizumab, nivolumab, and durvalumab as (potential) biomarker in immunotherapy, and several alternative preferred agents, regardless of PD-L1 expression. studies have investigated its predictive value in UCs. Table 1 (e European Medicines Agency (EMA) recently approved lists the clinical trials that evaluated PD-L1 expression by pembrolizumab for the treatment of metastatic/unresectable immunohistochemistry (IHC) or the IHC-based combined UCs in relapsed patients after first-line platinum-based positive score (CPS) to develop a reproducible PD-L1 therapy and also in nonpretreated cisplatin-unfit patients scoring method that can be used to identify patients most with CPS>10. (e EMA has also approved atezolizumab for the first- and second-line treatment of UC and nivolumab likely to respond to therapy. CPS is obtained as follows: CPS � 100 × PD-L1 stained cells (tumor cells, lymphocytes, for use in a second-line setting. Although the cancer vaccine, macrophages)/total viable tumor cells. In RCC, PD-L1 is not sipuleucel-T, has shown activity in prolonging OS in PCa, a useful predictor of response to ICI treatment. Both PD-L1- none of the new ICIs have been approved. (is is due to negative and PD-L1-positive tumors respond to immuno- limited antitumor immune infiltrates and poor PD-L1 ex- therapy, despite higher rates of RR and PFS in patients with pression in this tumor type [77, 78]. In germ-cell tumors, PD-L1 expression. In fact, in the metastatic RCC population PD-L1 expression has been observed in 73% and 64% of of the CheckMate 214 trial, the combination of nivolumab patients with seminoma and nonseminoma types, re- plus ipilimumab obtained an objective RR of 37% in patients spectively [79] and correlates with outcome. Low levels of with PD-L1 expression<1%, compared to 58% of those with PD-L1 are associated with better PFS [80]. Despite the PD-L1 expression >1% [31]. In the IMmotion 151 trial, prognostic value of PD-L1 expression, pembrolizumab has not shown activity as a single agent in the treatment of patients with PD-L1≥ 1% showed longer PFS when treated with bevacizumab plus atezolizumab [66]. Conversely, the refractory germ-cell tumors [81]. (erefore, PD-L1 is the combination of axitinib with pembrolizumab (KEYNOTE only recognized biomarker in patients with UC, but its 423 trial) or axitinib with avelumab (Javelin Renal 101) did prognostic and predictive role is still open to debate in not produce different efficacy results on the basis of different nonurothelial urological tumors. A recent study of 160 UC PD-L1 statuses [67, 68]. Similarly, Motzer et al. observed that patients showed that although PD-L1 positivity ≥5% in the use of nivolumab after treatment with anti-VEGFR tumor cells was not predictive of OS, it was predictive if inhibitors improved OS independently of PD-L1 status [69]. expressed in TIL cells [82]. Mariathasan et al., after evalu- Unlike RCC, PD-L1 has been recognized as a predictive ating data from the IMvigor 210 phase 2 trials, reported that differences in PD-L1 also existed between tumor cells and biomarker in UCs. In metastatic/locally advanced UC, atezolizumab and pembrolizumab demonstrated antitumor inflammatory cells in TILs [54]. Hence, the debate about the Journal of Oncology 5 Table 1: Potential predictive biomarkers in urological tumors treated with ICIs. Histology Biomarker Trial/author Drugs Setting Study results KEYNOTE 052 24% ORR, highest ORR in Urothelial PD-L1 (CPS) Pembrolizumab 1-line CDDP ineligible (phase 2) patients with CPS≥ 10% Higher ORR in KEYNOTE 045 Pembrolizumab vs Second line after pembrolizumab group PD-L1 (CPS) (phase 3) CHT platinum-based CHT than CHT, regardless of tumor PD-L1 expression ORR: 26% (PD-L1≥ 5%) ≥2-line after NCT02108652 vs 15% (all patients) PD-L1 (IHC) Atezolizumab platinum-based CHT (phase 2) OS: 11.4 (PD-L1≥ 5%) vs (cohort 2) 7.9 (all patients) months No significant enrichment NCT02108652 First-line CDDP PD-L1 (IHC) Atezolizumab of response and OS by (phase 2) ineligible PD-L1 expression Patients with higher PD- NCT01772004 ≥2-line treatment after L1≥ 5% showed higher PD-L1 (IHC) Avelumab (phase 1b) platinum-based CHT response rates and longer PFS and OS ORR: 28.4% (PD-L1≥ 5%) vs 23.8% (PD-L1≥ 1%) vs CheckMate 275 ≥2-line treatment after PD-L1 (IHC) Nivolumab 16.1 (PD-L1< 1%); OS: (phase 2) platinum-based CHT 11.3 (PD-L1≥ 1%) vs 5.9 (PD-L1< 1%) months CXCL9, CXCL10 CheckMate 275 ≥2-line treatment after Positive predictors of Nivolumab cytokines (phase 2) platinum-based CHT response to nivolumab Positive predictors of response to atezolizumab; PD-L1 expression on IC (>5% of cells) was CXCL9, CXCL10 ≥2-line after significantly associated cytokines PD-L1 rabbit IMvigor 210 (phase 2) Atezolizumab platinum-based CHT with response. In SP142 (Ventana) (cohort 2) contrast, PD-L1 expression in tumor cells was not associated with response No differences in PFS and NCT01693562 ≥2-line treatment after ORR between high and PD-L1 (IHC) Durvalumab (phase 2) platinum-based CHT low/negative PD-L1 patients dMMR caused a high G. Iyer et al., J Clin mutation load and was dMMR or MSI-H ICIs Metastatic setting Oncol 2017 associated to durable responses to ICIs Greater benefit in ORR, Nivolumab PFS, and OS for patients CheckMate 214 Kidney PD-L1 rabbit 28-8 (Dako) ipilimumab vs First line with PD-L1≥ 1% treated (phase 3) sunitinib with nivolumab and ipilimumab Greater benefit in ORR and PFS in patients with Avelumab plus treated with avelumab PD-L1 (IHC) Javelin renal 101 First line axitinib vs sunitinib plus axitinib, independently from PD- L1 Greater benefit in ORR, OS, and PFS in patients KEYNOTE 423 Pembrolizumab plus with treated with PD-L1 (IHC) First line (phase 3) axitinib vs sunitinib pembrolizumab plus axitinib, independently of PD-L1 6 Journal of Oncology Table 1: Continued. Histology Biomarker Trial/author Drugs Setting Study results PFS in PD-L1≥ 1% patients: 11.2 mo (with Bevacizumab/ PD-L1 (IHC) rabbit IMmotion 151 atezolizumab plus atezolizumab vs 1-line SP142 (Ventana) (phase 3) bevacizumab) vs 7.7 mo sunitinib (with sutent), HR 0.74, P � 0.0217 PD-L1 (IHC) rabbit 28-8 CheckMate 025 Nivolumab vs ≥2-line treatment after No differences in OS on (Dako) (phase 3) everolimus anti-VEGFR therapy the basis of PD-L1 status Normal body mass index De Giorgi et al., Clin Retrospective analysis ≥2-line treatment after SII rabbit 28-8 (Dako) combined with higher SII Cancer Research 2019 of EAP of nivolumab anti-VEGFR therapy tripled the risk of death ORR: 53% of patients and Le DT et al., Science Advanced dMMR complete responses were Prostate dMMR Pembrolizumab 2017 cancers achieved in 21% of patients PD-L1 � programmed death-ligand 1; CPS � combined positive score; ICIs � immune-checkpoint inhibitors; ICH � immunohistochemistry; SII � systemic inflammation index; dMMR � mismatch repair genes deficiency; MSI-H � higher microsatellite instability; CHT �chemotherapy; EAP � expanded access program; ORR � overall response rate; PFS � progression-free survival; OS � overall survival. different value of PD-L1 expression in tumor and nontumor prognosis and NLR and treatment response, its prognostic role remains uncertain [93, 94]. In UC and RCC, NLR is cells (TILs) is still open. significantly associated with prognosis [95–97]. As seen in breast cancer [98], lymphopenia is also associated with poor 3.2. Prognostic and Predictive Role of TIM-3, B7-H3, and prognosis in patients with RCC [99]. In a study on an elderly B7-H4. Tumor-associated macrophages induce a more mRCC population treated with first-line sunitinib, lym- immunosuppressive phenotype, leading to an enhanced phopenia proved to be a negative prognostic factor [100]. + + expression of TIM-3 and PD-1 on CD4 and CD8 T cells. (rombocytosis has also been identified as a negative (e concentration of TIM-3 and PD-1-positive CD4 and prognostic factor in RCC patients [101]. A recently pub- CD8 T cells is higher in TILs than in peripheral blood in lished study evaluated the role of SII in RCC patients treated RCC patients [83]. Recently, Granier et al. demonstrated that with the PD-1 inhibitor nivolumab and enrolled in an Italian + + + PD-1 Tim-3 CD8 T cells could not be enhanced in vitro by Expanded Access Program. (e authors demonstrated that a strong stimulus, suggesting that these cells cannot be normal body mass index combined with higher SII tripled reactivated after PD-1-PD-L1 blockade [84]. In PCa patients, the risk of death, suggesting that SII is a critical prognostic malignant cells show higher TIM-3 expression than benign factor for OS in pretreated RCC patients during treatment cells, expression correlating with TNM staging system, with nivolumab [102]. A recent article confirmed the grading, and PFS [85]. Piao et al. demonstrated that Tim-3 prognostic role of SII (and its variations during therapy) in expression in both CD4+ and CD8+ Tcells closely correlated mRCC patients treated with sunitinib [103]. Recently, a with advanced disease and poor prognosis in PCa patients study evaluated the combination of SII and the monocyte/ [86]. Other studies have evaluated the prognostic role B7-H3 lymphocyte ratio (MLR) as new prognostic factor in upper- and B7-H4 in UTs. In both RCC and PCa, the over- tract UC. (e authors demonstrated that SII was signifi- expression of B7-H3 and B7-H4 was correlated with poor cantly associated with PFS and OS, whereas MLR signifi- prognosis and a higher risk of recurrent and metastatic cantly correlated with OS but not with PFS. Both SII and disease [87, 88]. Moreover, in RCC, B7-H3 and B7-H4 were MLR correlate with an enhanced risk of disseminated disease expressed by both immune and endothelial cells: among 743 [104]. In PCa, Fan et al. reported that SII has a negative RCC patients, B7-H3-positive TILs were observed in 17% of independent prognostic role in terms of OS in patients tumor samples and in 95% of tumor vasculature [89]. treated with both abiraterone and docetaxel, independently Another study reported a B7-H4 positive expression in of the treatment sequence [105]. tumor vasculature of 211 RCC patients [90, 91]. In UCs, B7- H3 is overexpressed in all tumor stages and its expression 3.4. Predictive Role of IFN-c and Other Cytokines. A 25- can be stimulated by Bacillus Calmette–Guerin-based ´ gene IFN-c signature was evaluated in patients with met- therapy [92]. astatic UC enrolled in the phase II trial CheckMate 275, a trial focusing nivolumab used as a single agent. (e analysis 3.3. Prognostic Role of NLR and SII. In the last few years, demonstrated that a higher IFN-c signature was expressed in the prognostic role of NLR and SII has been evaluated in the basal-1 subgroup, corresponding to cluster III of the TCGA classification. (e patients in this group were more urological and nonurological cancers. Although several studies have demonstrated a correlation between NLR and likely to respond to ICIs [72, 73]. Recently, IFN-c-induced Journal of Oncology 7 cytokines (CXCL9 and CXCL10) were also shown to be remain: Why do some tumors express TILs and some do not? positive predictors of response to atezolizumab in the Why do some tumors not express PD-L1? What regulates IMvigor trial [71]. immune escape mechanisms? (e role of PD-1 and PD-L1 expression as a predictive biomarker is still unclear, the use of different methods and cutoff points in trials complicating its 3.5. Prognostic and Predictive Role of TMB and Genetic validation. As suggested by Mariathasan et al., another dif- Instability. In PCa, 2 large phase III trials on unselected ference may derive from different PD-L1 expressions in both patients reported the failure of anti-CTLA4 (ipilimumab) tumor cells and immune cells [54]. Moreover, patients with [106, 107]. Initial clinical data had shown that 5%–12% of low or negative PD-L1 expression respond to ICIs. Conse- patients with metastatic PCa may benefit from ICIs quently, more suitable biomarkers must be sought. In the near [108, 109], probably due to the low mutational loads of PCa, future, it is hoped that the biological characterization of which is correlated with low neoantigen burden [110]. (e tumors will be able to drive clinical decision-making, leading mismatch repair (MMR) gene is a DNA single-strand repair to more personalized treatment. In UCs, new classification mechanism. Mismatch repair-deficient (dMMR) cancers are systems such as TCGA will add further valuable information, characterized by microsatellite instability and hypermutator allowing for better patient selection. Furthermore, classifi- phenotype, both associated with chemotherapy resistance cation of biomarker expression into the three immunological but immunotherapy sensitivity [111]. In a study by Iyer et al., phenotypes “immune inflamed,” “immune excluded,” and dMMR or high MSI (MSI-H) were found in 3% of 424 UC “immune desert” could improve our knowledge of distinct patients [112], both subgroups showing a higher response to immunological pathways, enabling a more effective use of ICIs [112]. A recently published phase II trial including ICIs such as mono- or combination therapies [118]. patients with cholangiocarcinoma, colorectal, endometrial, In the past, nanoparticle-based drugs have been hypoth- gastric, and small bowel cancer demonstrated that dMMR esized for the treatment of cancer. (ese drug nanocarriers can predicted clinical benefit from pembrolizumab [20]. In PCa, improve the therapeutic efficacy of a drug by penetrating deep the prevalence of dMMR varies between 12% and 22% in into tissue and overcoming the physical barriers linked to drug different studies, probably because of the different assays release [119]. In this scenario, the identification of new cancer- used to detect the genomic aberrations [113, 114]. Recent specific biomarkers could lead to the development of new evidence that dMMR cancers may benefit from pem- nanocarrier drugs directed against cancer-specific driver brolizumab [20] has led to FDA approval of pembrolizumab biomarkers. In the near future, the identification of new for the treatment of metastatic/unresectable solid tumors biomarkers capable of predicting outcome and of acting as with dMMR or MSI-H in patients who progress on prior molecular targets for cancer treatment will be possible, thanks treatment. Initially, this indication included several cancer to a greater understanding of the intrinsic mechanisms that types but not PCa. After the results from the KEYNOTE- regulate immune system activity. Meanwhile, the search for 028-phase 1b trial were published [109], the FDA expanded new and reliable predictive biomarkers will proceed in 3 main the previous indication to include patients with pretreated directions: humoral (cytokines), immunohistochemical (new metastatic PCa with MSI-H or dMMR deficiency [115]. or unexplored checkpoints), and genomic (mutations, genetic However, dMMR cancers do not always respond to im- instability). munotherapy, and not all cancers responding to ICIs are dMMR [20, 21, 116]. In fact, a recent study showed that Conflicts of Interest dMMR tumors constitute a subtype with decreased survival time but that only a proportion has a high mutation load and Ugo De Giorgi has received personal fees for advisory board/ show PD-L1 IHC staining. (us, dMMR tumors represent a consultancy from Astellas, Bayer, BMS, Ipsen, Janssen, heterogeneous group and may require further sub- Merck, Novartis, Pfizer, and Sanofi. 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Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors

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Hindawi Journal of Oncology Volume 2019, Article ID 7317964, 11 pages https://doi.org/10.1155/2019/7317964 Review Article Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors 1 1 2 3 Giuseppe Schepisi , Nicole Brighi, Maria Concetta Cursano, Giorgia Gurioli, 4 1 1 4 1 GiorgiaRavaglia, AmeliaAltavilla, SalvatoreLucaBurgio, SaraTestoni, CeciliaMenna, 1 1 2 2 1 Alberto Farolfi, Chiara Casadei, Giuseppe Tonini, Daniele Santini, and Ugo De Giorgi Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Medical Oncology Department, Campus Bio-Medico University, Rome, Italy Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Correspondence should be addressed to Giuseppe Schepisi; giuseppe.schepisi@irst.emr.it Received 7 May 2019; Revised 28 August 2019; Accepted 6 September 2019; Published 19 September 2019 Guest Editor: Xuelei Ma Copyright © 2019 Giuseppe Schepisi et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secondary resistance to immunotherapy: tumor-derived protein and cytokines, tumor mutational burden, and patient performance status and comorbidities can condition tumor re- sponse to ICIs. Recently, some of these factors have been evaluated as potential biomarkers of response, with conflicting results. To date, the expression of programmed death-ligand 1 (PD-L1) and the presence of deficient mismatch repair (dMMR) in tumor tissue are the only biomarkers capable of guiding the clinician’s decision in urothelial cancer and prostate cancer, respectively. In this review, we performed a comprehensive search of the main publications on biomarkers that are predictive of response to ICIs in urological cancers. Our aim was to understand whether existing data have the potential to drive clinical decision-making in the near future. persists. According to the tumor immunity in the microen- 1. Introduction vironment (TIME) classification [1], tumors can be divided Immunotherapy is fast becoming the new frontier of on- into 4 subgroups based on the presence of inflammatory − − cology, accompanied by the dream of being able to defeat infiltrate (TIL) and PD-L1 expression: T1 (PD-L1 , TIL ), T2 + + − + + − cancer definitively. Although a substantial improvement in (PD-L1 , TIL ), T3 (PD-L1 , TIL ), and T4 (PD-L1 , TIL ) survival has been seen since immunotherapy was first used in (Figure 1). Although the TIME classification has significant melanoma, response remains low. (e use of different types of predictive implications, there is an increasing need to find immune-checkpoint inhibitors (ICIs), in particular the pro- predictive markers of response to ICIs. grammed death-1/programmed death-ligand 1 (PD-1/PD- L1) axis, has led to significantly better results in terms of 2. Factors Involved in Primary and Secondary response and manageability. In recent years, advances have Resistance to ICIs in Solid Tumors been made in the treatment of urological tumors, especially renal cell cancer (RCC) and urothelial cancer (UC). However, Several factors can directly or indirectly influence the im- the issue of the identification of nonresponding patients mune response and therefore contribute to triggering 2 Journal of Oncology Tumor cell – – + + T1: PD-L1 TIL T2: PD-L1 TIL Tumor-infiltrating – + + – lymphocyte (TIL) T3: PD-L1 TIL T4: PD-L1 TIL Programmed death-ligand 1 (PD-L1) Figure 1: Four tumor subtypes according to the TIME classification based on the expression of PD-L1 in tumor cells and on the presence of TILs. resistance mechanisms. As shown in Figure 2, these factors markers capable of activating the immune response. Con- can be divided into two categories: versely, a high expression of mutations, i.e., tumor muta- tional burden (TMB), especially if mismatch repair genes are (1) Patient-related factors: it is acknowledged that pa- involved, correlates with a high RR to ICIs, regardless of tients in poor clinical conditions have a lower immune histology [20–23]. In UC, a recent study showed a higher RR response. However, the underlying mechanism for in patients with alterations in the following genes: ATM, this is still not understood. In fact, Pan et al. reported BRCA2, ERCC2, FANCA, MSH6, and POLE [24]. However, that an Eastern Cooperative Oncology Group per- unlike solid tumors, elevated TMB has been associated with formance score (ECOG PS) of 2 in melanoma patients poor prognosis in hematological cancers, for example, was associated with worse prognosis when ICIs were multiple myeloma [25]. (e growing interest in TMB has led used [2]. Conversely, a study carried out on patients to the development of studies aimed at testing the efficacy of with UC treated with atezolizumab showed that re- neoantigens, structured within new molecules, such as sponse rates (RRs) did not differ among patients with chimeric antigen T-cell receptor therapy (CAR-T). Several different PS [3]. Recently, several trials conducted on studies are also underway for patients with RCC [26–28] and UC demonstrated a shorter overall survival (OS) in prostate tumors (PCa) [29]. patients with ECOG PS> 2 compared with ECOG PS PD-L1 expression in tumor tissue is one of the best 0 [3–6]. Several comorbidities can also affect the known mechanisms for neutralizing immune system ac- immune response: autoimmune diseases [7, 8], di- tivity. A higher PD-L1 expression results in a poorer abetes [9], transplantations [10–12] (including bone prognosis without the use of ICIs [13]. However, PD-L1 is marrow transplants), and infections [13]. Another not always capable of predicting response to ICIs [30, 31]. In important host-related factor is gut microbiota: sev- fact, although response rates in UC differ significantly on the eral studies have shown that restoration of some basis of PD-L1 status, this is not the case for RCC patients bacterial families (Ruminococcaceae [14], Akker- [32, 33]. mansia muciniphila [15], and Bacteroides fragilis [16]) To date, CTLA-4 and PD1/PD-L1 axis are not the only is correlated with a longer response in melanoma mice molecules involved in the modulation of the immune re- treated with anti-PD1 drugs. (us, the use of anti- sponse. Other molecules are currently under investigation as biotics or steroids during ICI therapy may affect the potential immune checkpoint for new ICIs, e.g., lymphocyte- outcome of treatment. In particular, 2 recent studies activation gene-3 (LAG-3), T-cell immunoglobulin mucin-3 [17, 18] showed that the use of beta-lactams, quino- (TIM-3), and B7-H3 and B7-H4/B7x/B7S1. lones, and macrolides during ICIs therapy also led to LAG-3 molecule is located on the cell surface of several shorter progression-free survival (PFS) and poorer RR immune cells; its ligand is Class II MHC and binds with in RCC patients. higher affinity than CD4 [34]. LAG-3 downregulates the + + (2) Tumor-related factors: this category can be divided immune response of CD4 - and CD8 -activated cells. In into 2 subcategories: intratumoral and microenvi- fact, its negative activity has been observed in CD8 tumor- ronmental factors. infiltrating lymphocytes (TILs) and in CD4 TRegs [35]. TIM-3 is a regulatory molecule expressed on the surface of innate immune cells; CD8 TILs usually coexpress PD-L1 2.1. Intratumoral Factors. Among tumor-related factors, and TIM-3, causing a strong inhibition of cytokine secretion [36]. To date, TIM-3/PD-L1 coexpression has also been different histologies and the presence of chromosomal al- terations influence the immune response. For example, studied in CD8 cells in melanoma patients. In one study, blocking both PD-L1 and TIM-3 led to a restoration of strongly aneuploid tumors have shown an intrinsic re- sistance to ICIs [19]. (is is due to the poor expression of cytokine secretion [37]. Journal of Oncology 3 Performance Comorbidities Status Tumor-related Intratumoral Microenviromental (i) Histology (i) TILs (ii) Chromosome alterations (ii) IDO (iii) TMB (iii) TGF-β (iv) PD-L1 (iv) CXCR3 ligands (CXCL9-CXCL10) (v) LAG-3 (v) NLR Gut microbiota (vi) TIM-3 (vi) SII (vii) B7-H3, B7-H4 Patient-related Figure 2: Factors influencing immune response and possibly related to resistance to immunotherapy. TMB: tumor mutational burden; PD- L1: programmed death-ligand 1; LAG-3: lymphocyte-activation gene-3; TIM-3: T-cell immunoglobulin and mucin domain 3; TILs: tumor- infiltrating lymphocytes; IDO: indoleamine-2,3-dioxygenase; TGF-β: transforming growth factor-β; CXCR: CXC chemokine receptors; CXCL: CXC chemokine receptors ligands; NLR: neutrophil-to-lymphocyte ratio; SII: systemic immune-inflammation index. B7-H3 and B7-H4 (also known as B7x/B7S1) are 2 anti-CTLA4 antibodies or CAR-T-cell therapy. However, members of the B7 super-family expressed not only by some negative PD-L1 tumors may respond to an anti-PD-L1 immune cells but also by nonlymphoid tissues, including drug. Positivity or negativity of the histological examination prostate and testis cells [38]. Although B7-H3 was initially may not reflect a common characteristic of the overall tumor. characterized as a costimulatory molecule, recent studies (us, tumor heterogeneity may be responsible for ICI re- have indicated its dual activity. In some cases, it acts as an sponse in patients with PD-L1-negative biopsy [1]. It is also a upregulator of the immune responses and in others, a unstable characteristic over time; in fact, treatment may select downregulator [39]. altered tumor cells capable of activating the process of im- mune escape, blocking the immune system activation, and even transforming positive TIL into negative TIL tumors. (is 2.2. Microenvironmental Factors. Tumor microenvironment condition has been described in different tumor types, such as plays an important role in silencing the immune response. lung and breast cancer and RCC [46–48]. In particular, Usually, the presence of TILs is related to higher PD-L1 discordance in PD-L1 status between primary and metastatic expression [40, 41] and to better response to ICI treatment sites has been observed in 20% of RCC patients [49]. (e [23]. (e KEYNOTE 028 study tested the efficacy of pem- immune-silencing process is ascribed to several mechanisms: brolizumab in 20 different tumors. Results showed that activation of the Wnt–β-catenin pathway [50]; loss of PTEN treatment with ICIs was more effective in patients with TILs, associated with AKT activation [51]; and loss of immuno- independently of tumor histology [42]. genicity [52] through several mechanisms (including On the other hand, the aforementioned TIME classifi- downregulation of MHC class I molecules and reduced cation [1] has emphasized the link between TILs and PD-L1 in production of immunogenic antigens). determining the response to ICIs. However, its correlation (e study of the tumor microenvironment has led to the with response in UTs is still under evaluation [43]. (e T2 discovery of other molecules involved in immune-silencing subgroup, for example, is characterized by the presence of mechanisms. For example, indoleamine-2,3-dioxygenase TILs and higher PD-L1 expression, stimulated by the TIL- (IDO) is a molecule produced in TILs capable of stimulating mediated production of interferon-gamma (IFN-c). (is the immune infiltrate, reducing the concentration of tryp- subgroup is associated with high RRs when treated with ICIs. tophan which is necessary for the activation of cytotoxic Unlike T2, the T3 subgroup expresses TILs but not PD-L1 T cells, and permitting their transformation into regulatory (probably due to a nonexpression of inducing factors, such as T cells (TRegs). (is promotes an immunosuppressive mi- IFN-c). In this context, the use of OX-40 or 4-1BB agonists croenvironment near the tumor. Consequently, IDO is a may convert tumors classified as T3 into T2 [44, 45]. T1 and promising biomarker, and high concentrations are associ- T4 subgroups differ because of their lack of TILs. Many ated with worse prognosis. However, IDO as a target for new tumors have this characteristic, which is usually associated drug development has been disappointing, and the use of with a nonresponse to treatment with ICIs. (ere are different ways to stimulate the immune response, for example, by using IDO inhibitors has not shown any advantages over ICI 4 Journal of Oncology treatment [53]. In addition to IDO, there is a high expression activity and acceptable tolerability in the first-line treatment of other molecules in tumor microenvironment, including of cisplatin-ineligible patients [3, 5]. Based on these results, the Food and Drug Administration (FDA) approved ate- TGF-β secreted by fibroblasts [54], and various other cy- tokines involved in immune-silencing mechanisms. Among zolizumab and pembrolizumab in this subgroup. However, these molecules, CXCL9 and CXCL10, two CXCR3 ligands, the FDA updated the prescribing information for first-line have shown to be correlated with the TIL-positive TIME pembrolizumab and atezolizumab in cisplatin-ineligible subgroups, whereas TIL-negative subgroups lack these patients, making it compulsory to use an approved PD-L1 chemokines [55, 56]. diagnostic test (Dako PDL-1 ICH 22C PharmDx Assay Furthermore, several studies have evaluated the prog- and Ventana PDL-1 Assay ) to select patients. (erefore, nostic/predictive role of some parameters, such as the FDA indications were modified as follows: cisplatin-unfit neutrophil-to-lymphocyte ratio (NLR) and the systemic patients are eligible for pembrolizumab and atezolizumab if immune-inflammation index (SII). NLR is the most widely the tumor expresses PD-L1 (CPS≥ 10 for pembrolizumab tested prognostic index and correlates with prognosis in and PD-L1≥ 5% for atezolizumab) [70]. In patients not different tumor types [57]. Similarly, SII, combining eligible for any platinum, pembrolizumab and atezolizumab neutrophils, lymphocytes, and platelet count in a single can be administered in first-line regardless of tumor PD-L1 parameter, demonstrates a significant correlation with expression. In postplatinum UC patients, several trials have prognosis in different cancers [58–60]. Among UTs, SII and demonstrated ICI efficacy [71–75], with ICI-treated PD-L1- NLR have shown a prognostic and predictive role of re- positive TIL-positive UCs showing higher RRs. In the sponse to conventional treatment in several retrospective IMvigor 210 trial, the use of atezolizumab obtained an trials [61–63]. In particular, Lalani et al. recently demon- overall response rate (ORR) of 16%, which was higher (28%) strated that an early reduction in NLR (at 6 weeks) was in patients with ≥5% PD-L1 expression [71]. In CheckMate associated with a significantly improved outcome in mRCC 275, patients with tumor cluster III proved most likely to patients after ICI treatment [64]. Moreover, Raccioppi et al. obtain a better response to nivolumab (30%) [73]. Similar found that preoperatory NLR value was a predictor of re- results were obtained in 2 other studies. In the JAVELIN sponse to BCG therapy in non-muscle-invasive bladder trial, avelumab demonstrated an ORR of 17% in all patients cancer [65]. and 50% in those showing PD-L1 expression [75]. In a phase 1/2 trial, durvalumab obtained an ORR of 31% in the overall population, 46% in patients with PD-L1 expression, and 0% 3. Potential Prognostic and Predictive in those without PD-L1 expression [76]. Based on these Biomarkers in UCs Treated with ICIs results, the FDA approved pembrolizumab as the preferred 3.1. PD-L1 and TILs. PD-L1 is the most widely studied drug, with atezolizumab, nivolumab, and durvalumab as (potential) biomarker in immunotherapy, and several alternative preferred agents, regardless of PD-L1 expression. studies have investigated its predictive value in UCs. Table 1 (e European Medicines Agency (EMA) recently approved lists the clinical trials that evaluated PD-L1 expression by pembrolizumab for the treatment of metastatic/unresectable immunohistochemistry (IHC) or the IHC-based combined UCs in relapsed patients after first-line platinum-based positive score (CPS) to develop a reproducible PD-L1 therapy and also in nonpretreated cisplatin-unfit patients scoring method that can be used to identify patients most with CPS>10. (e EMA has also approved atezolizumab for the first- and second-line treatment of UC and nivolumab likely to respond to therapy. CPS is obtained as follows: CPS � 100 × PD-L1 stained cells (tumor cells, lymphocytes, for use in a second-line setting. Although the cancer vaccine, macrophages)/total viable tumor cells. In RCC, PD-L1 is not sipuleucel-T, has shown activity in prolonging OS in PCa, a useful predictor of response to ICI treatment. Both PD-L1- none of the new ICIs have been approved. (is is due to negative and PD-L1-positive tumors respond to immuno- limited antitumor immune infiltrates and poor PD-L1 ex- therapy, despite higher rates of RR and PFS in patients with pression in this tumor type [77, 78]. In germ-cell tumors, PD-L1 expression. In fact, in the metastatic RCC population PD-L1 expression has been observed in 73% and 64% of of the CheckMate 214 trial, the combination of nivolumab patients with seminoma and nonseminoma types, re- plus ipilimumab obtained an objective RR of 37% in patients spectively [79] and correlates with outcome. Low levels of with PD-L1 expression<1%, compared to 58% of those with PD-L1 are associated with better PFS [80]. Despite the PD-L1 expression >1% [31]. In the IMmotion 151 trial, prognostic value of PD-L1 expression, pembrolizumab has not shown activity as a single agent in the treatment of patients with PD-L1≥ 1% showed longer PFS when treated with bevacizumab plus atezolizumab [66]. Conversely, the refractory germ-cell tumors [81]. (erefore, PD-L1 is the combination of axitinib with pembrolizumab (KEYNOTE only recognized biomarker in patients with UC, but its 423 trial) or axitinib with avelumab (Javelin Renal 101) did prognostic and predictive role is still open to debate in not produce different efficacy results on the basis of different nonurothelial urological tumors. A recent study of 160 UC PD-L1 statuses [67, 68]. Similarly, Motzer et al. observed that patients showed that although PD-L1 positivity ≥5% in the use of nivolumab after treatment with anti-VEGFR tumor cells was not predictive of OS, it was predictive if inhibitors improved OS independently of PD-L1 status [69]. expressed in TIL cells [82]. Mariathasan et al., after evalu- Unlike RCC, PD-L1 has been recognized as a predictive ating data from the IMvigor 210 phase 2 trials, reported that differences in PD-L1 also existed between tumor cells and biomarker in UCs. In metastatic/locally advanced UC, atezolizumab and pembrolizumab demonstrated antitumor inflammatory cells in TILs [54]. Hence, the debate about the Journal of Oncology 5 Table 1: Potential predictive biomarkers in urological tumors treated with ICIs. Histology Biomarker Trial/author Drugs Setting Study results KEYNOTE 052 24% ORR, highest ORR in Urothelial PD-L1 (CPS) Pembrolizumab 1-line CDDP ineligible (phase 2) patients with CPS≥ 10% Higher ORR in KEYNOTE 045 Pembrolizumab vs Second line after pembrolizumab group PD-L1 (CPS) (phase 3) CHT platinum-based CHT than CHT, regardless of tumor PD-L1 expression ORR: 26% (PD-L1≥ 5%) ≥2-line after NCT02108652 vs 15% (all patients) PD-L1 (IHC) Atezolizumab platinum-based CHT (phase 2) OS: 11.4 (PD-L1≥ 5%) vs (cohort 2) 7.9 (all patients) months No significant enrichment NCT02108652 First-line CDDP PD-L1 (IHC) Atezolizumab of response and OS by (phase 2) ineligible PD-L1 expression Patients with higher PD- NCT01772004 ≥2-line treatment after L1≥ 5% showed higher PD-L1 (IHC) Avelumab (phase 1b) platinum-based CHT response rates and longer PFS and OS ORR: 28.4% (PD-L1≥ 5%) vs 23.8% (PD-L1≥ 1%) vs CheckMate 275 ≥2-line treatment after PD-L1 (IHC) Nivolumab 16.1 (PD-L1< 1%); OS: (phase 2) platinum-based CHT 11.3 (PD-L1≥ 1%) vs 5.9 (PD-L1< 1%) months CXCL9, CXCL10 CheckMate 275 ≥2-line treatment after Positive predictors of Nivolumab cytokines (phase 2) platinum-based CHT response to nivolumab Positive predictors of response to atezolizumab; PD-L1 expression on IC (>5% of cells) was CXCL9, CXCL10 ≥2-line after significantly associated cytokines PD-L1 rabbit IMvigor 210 (phase 2) Atezolizumab platinum-based CHT with response. In SP142 (Ventana) (cohort 2) contrast, PD-L1 expression in tumor cells was not associated with response No differences in PFS and NCT01693562 ≥2-line treatment after ORR between high and PD-L1 (IHC) Durvalumab (phase 2) platinum-based CHT low/negative PD-L1 patients dMMR caused a high G. Iyer et al., J Clin mutation load and was dMMR or MSI-H ICIs Metastatic setting Oncol 2017 associated to durable responses to ICIs Greater benefit in ORR, Nivolumab PFS, and OS for patients CheckMate 214 Kidney PD-L1 rabbit 28-8 (Dako) ipilimumab vs First line with PD-L1≥ 1% treated (phase 3) sunitinib with nivolumab and ipilimumab Greater benefit in ORR and PFS in patients with Avelumab plus treated with avelumab PD-L1 (IHC) Javelin renal 101 First line axitinib vs sunitinib plus axitinib, independently from PD- L1 Greater benefit in ORR, OS, and PFS in patients KEYNOTE 423 Pembrolizumab plus with treated with PD-L1 (IHC) First line (phase 3) axitinib vs sunitinib pembrolizumab plus axitinib, independently of PD-L1 6 Journal of Oncology Table 1: Continued. Histology Biomarker Trial/author Drugs Setting Study results PFS in PD-L1≥ 1% patients: 11.2 mo (with Bevacizumab/ PD-L1 (IHC) rabbit IMmotion 151 atezolizumab plus atezolizumab vs 1-line SP142 (Ventana) (phase 3) bevacizumab) vs 7.7 mo sunitinib (with sutent), HR 0.74, P � 0.0217 PD-L1 (IHC) rabbit 28-8 CheckMate 025 Nivolumab vs ≥2-line treatment after No differences in OS on (Dako) (phase 3) everolimus anti-VEGFR therapy the basis of PD-L1 status Normal body mass index De Giorgi et al., Clin Retrospective analysis ≥2-line treatment after SII rabbit 28-8 (Dako) combined with higher SII Cancer Research 2019 of EAP of nivolumab anti-VEGFR therapy tripled the risk of death ORR: 53% of patients and Le DT et al., Science Advanced dMMR complete responses were Prostate dMMR Pembrolizumab 2017 cancers achieved in 21% of patients PD-L1 � programmed death-ligand 1; CPS � combined positive score; ICIs � immune-checkpoint inhibitors; ICH � immunohistochemistry; SII � systemic inflammation index; dMMR � mismatch repair genes deficiency; MSI-H � higher microsatellite instability; CHT �chemotherapy; EAP � expanded access program; ORR � overall response rate; PFS � progression-free survival; OS � overall survival. different value of PD-L1 expression in tumor and nontumor prognosis and NLR and treatment response, its prognostic role remains uncertain [93, 94]. In UC and RCC, NLR is cells (TILs) is still open. significantly associated with prognosis [95–97]. As seen in breast cancer [98], lymphopenia is also associated with poor 3.2. Prognostic and Predictive Role of TIM-3, B7-H3, and prognosis in patients with RCC [99]. In a study on an elderly B7-H4. Tumor-associated macrophages induce a more mRCC population treated with first-line sunitinib, lym- immunosuppressive phenotype, leading to an enhanced phopenia proved to be a negative prognostic factor [100]. + + expression of TIM-3 and PD-1 on CD4 and CD8 T cells. (rombocytosis has also been identified as a negative (e concentration of TIM-3 and PD-1-positive CD4 and prognostic factor in RCC patients [101]. A recently pub- CD8 T cells is higher in TILs than in peripheral blood in lished study evaluated the role of SII in RCC patients treated RCC patients [83]. Recently, Granier et al. demonstrated that with the PD-1 inhibitor nivolumab and enrolled in an Italian + + + PD-1 Tim-3 CD8 T cells could not be enhanced in vitro by Expanded Access Program. (e authors demonstrated that a strong stimulus, suggesting that these cells cannot be normal body mass index combined with higher SII tripled reactivated after PD-1-PD-L1 blockade [84]. In PCa patients, the risk of death, suggesting that SII is a critical prognostic malignant cells show higher TIM-3 expression than benign factor for OS in pretreated RCC patients during treatment cells, expression correlating with TNM staging system, with nivolumab [102]. A recent article confirmed the grading, and PFS [85]. Piao et al. demonstrated that Tim-3 prognostic role of SII (and its variations during therapy) in expression in both CD4+ and CD8+ Tcells closely correlated mRCC patients treated with sunitinib [103]. Recently, a with advanced disease and poor prognosis in PCa patients study evaluated the combination of SII and the monocyte/ [86]. Other studies have evaluated the prognostic role B7-H3 lymphocyte ratio (MLR) as new prognostic factor in upper- and B7-H4 in UTs. In both RCC and PCa, the over- tract UC. (e authors demonstrated that SII was signifi- expression of B7-H3 and B7-H4 was correlated with poor cantly associated with PFS and OS, whereas MLR signifi- prognosis and a higher risk of recurrent and metastatic cantly correlated with OS but not with PFS. Both SII and disease [87, 88]. Moreover, in RCC, B7-H3 and B7-H4 were MLR correlate with an enhanced risk of disseminated disease expressed by both immune and endothelial cells: among 743 [104]. In PCa, Fan et al. reported that SII has a negative RCC patients, B7-H3-positive TILs were observed in 17% of independent prognostic role in terms of OS in patients tumor samples and in 95% of tumor vasculature [89]. treated with both abiraterone and docetaxel, independently Another study reported a B7-H4 positive expression in of the treatment sequence [105]. tumor vasculature of 211 RCC patients [90, 91]. In UCs, B7- H3 is overexpressed in all tumor stages and its expression 3.4. Predictive Role of IFN-c and Other Cytokines. A 25- can be stimulated by Bacillus Calmette–Guerin-based ´ gene IFN-c signature was evaluated in patients with met- therapy [92]. astatic UC enrolled in the phase II trial CheckMate 275, a trial focusing nivolumab used as a single agent. (e analysis 3.3. Prognostic Role of NLR and SII. In the last few years, demonstrated that a higher IFN-c signature was expressed in the prognostic role of NLR and SII has been evaluated in the basal-1 subgroup, corresponding to cluster III of the TCGA classification. (e patients in this group were more urological and nonurological cancers. Although several studies have demonstrated a correlation between NLR and likely to respond to ICIs [72, 73]. Recently, IFN-c-induced Journal of Oncology 7 cytokines (CXCL9 and CXCL10) were also shown to be remain: Why do some tumors express TILs and some do not? positive predictors of response to atezolizumab in the Why do some tumors not express PD-L1? What regulates IMvigor trial [71]. immune escape mechanisms? (e role of PD-1 and PD-L1 expression as a predictive biomarker is still unclear, the use of different methods and cutoff points in trials complicating its 3.5. Prognostic and Predictive Role of TMB and Genetic validation. As suggested by Mariathasan et al., another dif- Instability. In PCa, 2 large phase III trials on unselected ference may derive from different PD-L1 expressions in both patients reported the failure of anti-CTLA4 (ipilimumab) tumor cells and immune cells [54]. Moreover, patients with [106, 107]. Initial clinical data had shown that 5%–12% of low or negative PD-L1 expression respond to ICIs. Conse- patients with metastatic PCa may benefit from ICIs quently, more suitable biomarkers must be sought. In the near [108, 109], probably due to the low mutational loads of PCa, future, it is hoped that the biological characterization of which is correlated with low neoantigen burden [110]. (e tumors will be able to drive clinical decision-making, leading mismatch repair (MMR) gene is a DNA single-strand repair to more personalized treatment. In UCs, new classification mechanism. Mismatch repair-deficient (dMMR) cancers are systems such as TCGA will add further valuable information, characterized by microsatellite instability and hypermutator allowing for better patient selection. Furthermore, classifi- phenotype, both associated with chemotherapy resistance cation of biomarker expression into the three immunological but immunotherapy sensitivity [111]. In a study by Iyer et al., phenotypes “immune inflamed,” “immune excluded,” and dMMR or high MSI (MSI-H) were found in 3% of 424 UC “immune desert” could improve our knowledge of distinct patients [112], both subgroups showing a higher response to immunological pathways, enabling a more effective use of ICIs [112]. A recently published phase II trial including ICIs such as mono- or combination therapies [118]. patients with cholangiocarcinoma, colorectal, endometrial, In the past, nanoparticle-based drugs have been hypoth- gastric, and small bowel cancer demonstrated that dMMR esized for the treatment of cancer. (ese drug nanocarriers can predicted clinical benefit from pembrolizumab [20]. In PCa, improve the therapeutic efficacy of a drug by penetrating deep the prevalence of dMMR varies between 12% and 22% in into tissue and overcoming the physical barriers linked to drug different studies, probably because of the different assays release [119]. In this scenario, the identification of new cancer- used to detect the genomic aberrations [113, 114]. Recent specific biomarkers could lead to the development of new evidence that dMMR cancers may benefit from pem- nanocarrier drugs directed against cancer-specific driver brolizumab [20] has led to FDA approval of pembrolizumab biomarkers. In the near future, the identification of new for the treatment of metastatic/unresectable solid tumors biomarkers capable of predicting outcome and of acting as with dMMR or MSI-H in patients who progress on prior molecular targets for cancer treatment will be possible, thanks treatment. Initially, this indication included several cancer to a greater understanding of the intrinsic mechanisms that types but not PCa. After the results from the KEYNOTE- regulate immune system activity. Meanwhile, the search for 028-phase 1b trial were published [109], the FDA expanded new and reliable predictive biomarkers will proceed in 3 main the previous indication to include patients with pretreated directions: humoral (cytokines), immunohistochemical (new metastatic PCa with MSI-H or dMMR deficiency [115]. or unexplored checkpoints), and genomic (mutations, genetic However, dMMR cancers do not always respond to im- instability). munotherapy, and not all cancers responding to ICIs are dMMR [20, 21, 116]. In fact, a recent study showed that Conflicts of Interest dMMR tumors constitute a subtype with decreased survival time but that only a proportion has a high mutation load and Ugo De Giorgi has received personal fees for advisory board/ show PD-L1 IHC staining. (us, dMMR tumors represent a consultancy from Astellas, Bayer, BMS, Ipsen, Janssen, heterogeneous group and may require further sub- Merck, Novartis, Pfizer, and Sanofi. 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