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Hindawi Journal of Oncology Volume 2019, Article ID 5981054, 6 pages https://doi.org/10.1155/2019/5981054 Review Article The Therapeutic Strategies of Regulatory T Cells in Malignancies and Stem Cell Transplantations 1 2 Rana G. Zaini and Amani A. Al-Rehaili Deanship of Community Service and Sustainable Development, Taif University, Taif, Saudi Arabia College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia Correspondence should be addressed to Amani A. Al-Rehaili; firstname.lastname@example.org Received 24 July 2018; Revised 9 October 2018; Accepted 2 December 2018; Published 1 January 2019 Academic Editor: om Th as R. Chauncey Copyright © 2019 Rana G. Zaini and Amani A. Al-Rehaili. This 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. Regulatory T cells (Treg cells) are considered one of the main dynamic cell types within the immune system. Because Treg cells suppress immune responses, they have potential roles in immunological self-tolerance and may help to maintain immune homeostasis. Promoting Treg cell function and increasing their numbers might be useful in treating autoimmune disorders, as well as preventing allograft rejection. However, studies of mice and humans demonstrate that Treg cells promote cancer progression and suppress antitumor immunity. er Th efore, suppressing Treg cell function or reducing their numbers could support the immune system’s response to pathogenic microorganisms and tumors. As a result, there is great interest in investigating the Treg cells role in the treatment of hematological and nonhematological malignancies. Consequently, Treg cells could be a fundamentally important target for pathologies of the immune system. Targeting eeff ctor Treg cells could help to distinguish and selectively decrease these cells while preserving other Treg cells needed to suppress autoimmunity. Currently, a promising way to treat malignancies and other autoimmune disorders is stem cell transplantation. Stem cell transplants (SCT) can help to manage the production of Treg cells and also may produce more efficient Treg cells, thereby suppressing clinical disease progression. Specifically, mature T cells within the engraeft d stem cells mediate this SCT beneficial eeff ct. During SCT, the recipient’s immune system is replaced with a donor, which allows for improved immune system function. In addition, SCT can protect from disease relapse, as graft-versus- host disease (GvHD) in transplant patients can be protective against cancer recurrence. eTh current review will define the role of regulatory T cells in treatment of malignancy. Additionally, it will summarize current promising research regarding the utility of regulatory T cells in stem cell transplantation. 1. Introduction immune homeostasis [4, 5]. Moreover, they stimulate further effector immune cells such as CD8 cytotoxic T cells, B The immune system has vital mechanisms that eliminate cells, and macrophages in order to regulate adaptive immune microbes and diseased cells. At the same time, different responses to microorganisms and cancer . Regulatory T mechanisms maintain control of effector cells aer ft their (Treg) cells are also identified as suppressor T cells that activation by a physiologic inflammatory process . Inflam- can suppress possibly harmful Th cells’ actions . Gershon mation must be efficiently regulated to prevent excessive first described this in the 1970s . Treg cells are critical in immune reaction. Through cytokine stimulation, CD4+ preserving immunological tolerance. They play an essential na¨ıve T cells differentiate into two distinct lineages that role in reducing T cell-mediated immunity in order to end have different developmental pathways and unique biological the immune effects and to reduce autoreactive T cells [8, 9]. functions. These two types of T cells are helper/effector (Th) The major differences between Th cells and Treg cells is that and regulatory T (Treg) cells [2, 3]. Effector/helper T cells are effector T cell sets generally promote an immune response the fundamental participants in directing immune reactions. through their ability to initiate with immune-enhancing They are crucial in battling pathogens and maintaining cytokines and then shift to inhibitory cytokines later in their 2 Journal of Oncology life cycle, whereas Treg cells typically help to moderate and highly suitable to provide the assay of Treg quantitation . neutralize the immune response (i.e., immune-suppressive) They found that within IL2–treated melanoma patients and . The greatest noticeable role of Treg cells is maintaining patients with various solid tumor such as lung and colon carcinomas, the numbers of Treg cells significantly increased self-tolerance immunity and immune homeostasis by reduc- ing the immune response [7, 11–14]. u Th s, any failure in Treg . At the same time, they revealed that application of ther- cell function could result an excess of inflammatory and apeutic antibodies as immunosuppressive therapy resulted in a substantial decline in Treg from the peripheral blood of autoimmune diseases . Treg cells are subgroup a group of CD4 T cell com- transplantation patients . partments that can be originated from the thymus (i.e., Although Treg cells have an essential role in maintaining called naturally occurring Treg (nTreg) cells) or can be immune homeostasis, they also promote cancer progression produced from immature T cells in the presence of IL-2 and and suppress antitumor immunity in studies of mice [22, 23, 26, 27] and humans [28–30]. Enhancing the function Transforming growth factor-𝛽 (TGF-𝛽 ) following the prompt of T cell receptors (i.e., called induced Treg (iTreg) cells) of Treg cells or increasing their numbers could be valuable . They are characterized by coexpression of CD4+ and in treating allergic and autoimmune disorders, as well as in preventing allograft rejection. On the other hand, suppressing CD25+. These markers are believed to be important in the stimulation of immunological tolerance. Moreover, several Treg cell function or reducing their numbers could help surface markers have been reported for the suppression of support the immune system’s response against pathogenic microorganisms and tumors . u Th s, Treg cells could be Treg cells function. These include CD25+, a subunit of IL-2 receptor (IL-2R), CD4+, CTLA-4, CD73+, and CD39+ [17, fundamentally important in immunopathogenesis, since they 18]. The identification and isolation of Treg cells commonly may have a role as a therapy for immunological disorders and depend on exploiting the CD4+ and CD25+ expression, malignancies. typically with flow cytometric analysis . Almost a decade The current review will debate the regulatory T cells role in treatment of malignancies. It will also summarize the cur- ago, the transcription factor Forkhead box P3 (FoxP3) has been detected on Treg cells. FoxP3 has a fundamental role in rent possible uses of these cells in stem cell transplantation. controlling the process of inafl mmation . However, CD25+ is not a specific marker of Treg cells because simply expressing 2. Treg Cells in Animal and Human Studies CD25+ does not guarantee induction of the suppressor phenotype as they also presented on normal activated T cells It has been previously mentioned in this review that Treg . Consequently, it is difficult to distinguish between these cells have a vital role in the prevention of autoimmunity cells by flow cytometry only. Nevertheless, FoxP3+ cells have through their capability to inhibit T cells proliferation and been recently shown that they express a subunit of IL-7R, the cytokines production. However, depletion of Treg cells called CD127, in a notably low density . Unfortunately, the due to a mutation of the gene for transcription factor FoxP3 intracellular location of FoxP3 makes it difficult to identify can lead to serious autoimmune disorders [32, 33]. A study in by flow cytometry [22, 23]. u Th s, this marker should be scurfy mice by Bennett et al. (2001) determined that the loss of identified after cell permeabilization, but this is not practical FoxP3 protein and nTreg cells due to mutations in the FoxP3 for routine clinical laboratory testing [22, 23]. gene led to CD4+ T cells hyperactivation, causing early onset However, a study by Baron et al. (2007) suggests that of organ-specicfi autoimmune pathology . Similarly, the demethylation of the Treg-Specific Demethylated Region expression of low amounts of FoxP3 protein in Treg cells has stabilizes (TSDR) FOXP3, is a unique phenotype for Treg been found to be significantly associated with impaired sup- cells, and does not appear in rapid expression of FOXP3 pressor cell function . Interestingly, mice that overexpress on activated T cells. us Th , evaluation of these cells by FoxP3 have amplified nTreg cell development, which stops methylation methods provides a good benefit compared to the progression of lymphoproliferative syndrome and type the investigation of protein synthesis and gene expression one diabetes in mice deficient in nonobese diabetic (NOD) . Particularly, Baron et al. (2007) used a genome-wide and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) differential methylation hybridization analysis. Essentially, mice, respectively . their study revealed that despite expression of FOXP3 on The relationship of Treg cells and cancer situation is dif- activated T cells and those treated with Transforming growth ferent from autoimmune disease. Enhanced number of Treg factor beta (TGF-𝛽 ), these cells exposed no demethylation cells might support the tumor progression and impact on the for FOXP DNA, whereas subgroups of Treg that were stable disease course; therefore both the proportion and function of even upon extended in vitro expansion remained demethy- Treg cells are essential factors at cancer environment [31, 36]. lated. Collectively, they concluded that DNA demethylation A study by Viehl et al. (2006) has shown that there is an constitutes the best current consistent measurement for Treg increase in the Tregs frequency within tumor-bearing mice cells . and the suppression or depletion of these cells can improve Detection and quantification of Treg cells within periph- their antitumor immunity . A study using a murine eral blood or tissues associated with diseases are considered fibrosarcoma model showed that elevated Treg cells levels fundamental processes in understanding the role of these were detected at late stages of cancer, implying they may have cells in tissue sites. Wieczorek et al. (2009) extended Baron et a role in cancer progression . al. (2007) study and investigated the possibility of using the Human research has also shown that a genetic defect aforementioned method to measure Treg cells, which looked of the FoxP3 gene can prevent the Treg cells development, Journal of Oncology 3 leading to ranges of autoimmune diseases and severe allergies ... Studies of OX Surface Molecule. OX40 (CD134) is a type of the tumor necrosis factor receptor groups. OX40 is [1,38].Thereis accumulative evidence demonstrating that present on activated T cells, Treg cells, other lymphoid cells, FoxP3+CD25+CD4+Treg cells prevent immune responses and nonlymphoid cells . Triggering of OX40 signalling to cancerous cells  and further demonstrating the Treg with anti-OX40 mAbs (i.e., agonistic antibody) has been cells role in promoting tumour growth through inhibiting found to reduce the inhibitory activity of Treg cells . vaccine-stimulated antitumor immune reactions and pre- Another study showed that administration of anti-OX40 venting successful tumor control. us, Th the elevated CD4+ monoclonal Ab promoted robust suppression of tumor pro- CD25 T cells percentage was detected in patients diagnosed gression . The same study showed that OX40 signalling with melanoma [40, 41], gastric [42, 43], and ovarian cancers could amend the actions of effector T and Treg cells by [13, 44, 45]. Similarly, Liyanage et al. (2002) found that the reducing the suppressive activity of Treg cells and stimulating levels of Treg cells were notably greater in patients with breast the function of eeff ctor T cells . Collectively, stimulating cancer  and pancreatic cancer [46–49]. OX40 signalling could be useful in regulating the inhibitory effects of Treg cells, thereby preventing tumor growth. 3. Therapeutic Uses of Regulatory ... Studies of Combination of Tumor Site-Located CTL- T Cells in Cancer Associated Antigen- (CTLA-). CTLA-4 is presented on activated T cells as a negative immunomodulator. During This review will discuss several studies, which investigate immune responses, CTLA-4 provides inhibitory signalling the modification of Treg cells as a therapy for malignancy. mechanism. It is also particularly expressed by Treg cells The most recent studies suggest targeting molecules specific and is mediated following the stimulation process of TCR. to Treg cells and attempting to either deplete or modify Although the significance of CTLA-4 for Treg cells role is yet thefunction of these cells onceidentiefi d. Thesetargeted under debate, it has been stated that obstruction of CTLA- molecules include OX-40, CTLA-4, GITR, CCR4, PD-1, 4 signalling terminates the Treg cells’ suppressive activity LAG3, CD25, and CD15s. . Recently, it has been shown that using conditional knockout mice has demonstrated that lack of CTLA-4 in Treg cells prevents immune system self-tolerance and impairs .. Targeting T Cell Receptor Signalling Molecules and the inhibitory role of Treg cells in tumor immunity [58, 59]. Depleting the Regulatory T Cell Population Furthermore, in mice, selectively blocking CTLA-4 signalling mechanism in non-Treg T cells or Treg cells reveals that ... Studies of Folate Receptor (FR). A possible way CTLA-4 is needed for both Treg cells and activated effector to enhance tumor immunity by modifying Treg cells is to T cells. This blocking enhances tumor suppression by dimin- target the T cells receptor (TCR) signalling molecules. An ishing the suppressor activity of Treg cell and amplifying example of a TCR signalling molecule is the Folate Receptor the function of eeff ctor T cell [58, 59]. Mainly, CTLA4 4 (FR4) . FoxP3+Treg cells in rodents express a higher stabilizes the function of CD28 (i.e., the T cell costimulatory FR4 level as compared to na¨ıve T cells. Additionally, during receptor). CD28 does not affect the stimulation of T cell the process of TCR stimulation, greater proportions of FR4 unless the TCR is initially engaged by related antigen. After are upregulated than na¨ıve T cells (i.e., FoxP3−T cells). This antigen recognition happens, CD28 signalling powerfully enables the activated effector T cells to be easily differentiated increases TCR signalling to activate T cells. CD28 and from activated Treg cells. Accordingly, an anti-FR4 depleting CTLA4 allocate same ligands: CD80 and CD86. Whereas the monoclonal antibody could be valuable to promote immunity particular CTLA4 mechanisms are still not fully understood, of tumors through diminishing activated Treg cells whereas because CTLA4 has a much superior overall affinity for both maintaining tumor-reactive effector T cells . ligands, it has been suggested that its expression on the T cells surface reduces the T cells activation by outweighing CD28 in binding CD80 and CD86 and actively producing .. Targeting T Cell Signalling Molecules and Modifying suppressive signals to the T cell . The therapeutic use of Function of the Treg Cell Population anti-CTLA4 mAb helps to regulate Treg cells and it possibly serves as promising approach to develop antitumor response. ... Studies of Glucocorticoid-Induced Tumor Necrosis Factor For example, the combined use of anti-GITR mAb and Receptor (GITR) Surface Molecule. GITR is a molecule highly anti-CTLA-4 mAb provoked a high eeff ctive response of presented by Treg cells that could be targeted to modulate antitumor than mAb alone, causing regression of advanced Treg cell function. Mice studies have demonstrated that appli- stage tumors . cation of anti-GITR antibody (nondepleting) can decrease the inhibition activities of Treg cells and increase the eeff ctor 4. Stem Cell Transplantation as a function of other T cell types to break the self-tolerance immunity [52, 53]. Additionally, this antibody can also trigger Therapeutic Approach to Modify Regulatory antitumor immunity by increasing the amount of IFN-𝛾 - T Cells in Malignancies yielding CD4+ and CD8+ T cells . Currently, clinical trials have been examined the use of anti-GITR antibodies in It has been well established that hematopoietic stem cell patients with progression of solid tumors, such as melanoma transplantation (SCT) is useful in hematological malig- . nancies as well as nonmalignant hematological disorders. 4 Journal of Oncology Chemotherapy and/or radiotherapy destroys a patient’s the balance between the two cell populations. This combi- hematopoietic system and enhances immunosuppression to nation therapy can suppress Treg cells and simultaneously engraft donor stem cells . Donor immune cells facilitate increase effector T cell activity. Accordingly, the new cancer the engraftment of stem cells, protect against infections, and treatments with regard to Treg cells management could most importantly destroy the remaining hematopoietic cells include blocking their trafficking into tumors, depletion, or of the host. In addition, this process protects from disease diminishing their differentiation and mediating their mech- retrogression during transplantation occurring in patients anisms. More work is still needed to create proper protocols, with leukemia or lymphoma, known as the gra-ft versus- including correct biomarkers, for monitoring of treatment leukemia effect . efficacy. Currently, stem cell transplantation promises to treat The success of SCT depends on the substitution of the a variety of malignancies and other autoimmune disorders. recipient’s immune system with the immune system cells To suppress disease progression, with early management of production and efficacy of Treg cells, these cells are actively of donor. Specifically, mature T cells within the engrafted stem cells mediate this SCT beneficial effect . However, being investigated as a way to improve SCT. Collectively, it the donor’s T cells can also attack the recipient’s tissues is now clear that there is proof from both animal and human and generate a life-threatening syndrome called graft-versus- studies that the Treg cells have a pivotal role at cancer context. host disease (GvHD) . The SCT challenge is to make They have a substantial role in cancer progression, and they a balance between the harmful effects and the beneficial T have a signicfi ant role destroying tumor immunity. u Th s, the cells, which is currently only insufficiently achieved with future researches in terms of malignancies treatments should immunosuppressive drugs. These Treg cells decrease GvHD focus on developing new clinical approaches to decrease their whereas maintaining the graft-versus-leukemia (GVL) effect regulatory effects, along with the essential goal of enhancing in various mouse model systems. Their use in the clinical their antitumor immunity. trials of SCT may be shortly studied, as their characterization in humans is rapidly progressing . Conflicts of Interest Treg cells have been shown to have potential in preventing GvHD in hematopoietic stem cell transplantation (HSCT). The authors declare that they have no conflicts of interest. 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