Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Tregs have a role in immunological tolerance and immune homeostasis by suppressing immune reactions, and its therapeutic potential is critical in autoimmune diseases and cancers. There have been multiple studies conducted on Tregs because of their roles in immune suppression and therapeutic potential. In tumor immunity, Tregs can promote the development and progression of tumors by preventing effective anti-tumor immune responses in tumor-bearing hosts. High infiltration of Tregs into tumor tissue results in poor survival in various types of cancer patients. Identifying factors specifically expressed in Tregs that affect the maintenance of stability and function of Tregs is important for understanding cancer pathogenesis and identifying therapeutic targets. Thus, manipulation of Tregs is a promising anticancer strategy, but finding markers for Treg-specific depletion and controlling these cells require fine-tuning and further research. Here, we discuss the role of Tregs in cancer and the development of Treg-targeted therapies to promote cancer immunotherapy.

[1]  Reem Saleh,et al.  Treg-mediated acquired resistance to immune checkpoint inhibitors. , 2019, Cancer letters.

[2]  Hiromasa Morikawa,et al.  PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer , 2019, Proceedings of the National Academy of Sciences.

[3]  E. Gianchecchi,et al.  Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression , 2018, Front. Immunol..

[4]  H. Wada,et al.  Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment , 2018, Journal of Immunotherapy for Cancer.

[5]  P. Iversen,et al.  Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade , 2018, Journal of Immunotherapy for Cancer.

[6]  Angela E. Leek,et al.  Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies , 2018, Cancer cell.

[7]  A. Rogel,et al.  The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. , 2018, Blood.

[8]  J. Schlom,et al.  Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors , 2018, Clinical Cancer Research.

[9]  Chenxi Hu,et al.  The role and significance of VEGFR2+ regulatory T cells in tumor immunity , 2017, OncoTargets and therapy.

[10]  Abhishek S. Rao,et al.  Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors. , 2017, JCI insight.

[11]  J. Kirkwood,et al.  Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity , 2017, Cell.

[12]  J. Burke,et al.  Phase 1 safety of ICOS agonist antibody JTX-2011 alone and with nivolumab (nivo) in advanced solid tumors; predicted vs observed pharmacokinetics (PK) in ICONIC. , 2017 .

[13]  T. Kurosaki,et al.  BACH transcription factors in innate and adaptive immunity , 2017, Nature Reviews Immunology.

[14]  S. Khleif,et al.  Differential PI3Kδ Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy. , 2017, Cancer research.

[15]  V. Kuchroo,et al.  Tim‐3 and its role in regulating anti‐tumor immunity , 2017, Immunological reviews.

[16]  Y. Doki,et al.  ICOS+ Foxp3+ TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori , 2017, International journal of cancer.

[17]  Jason B. Williams,et al.  The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment , 2017, The Journal of experimental medicine.

[18]  S. Sakaguchi,et al.  Regulatory T cells in cancer immunotherapy , 2016, Cell Research.

[19]  H. Stunnenberg,et al.  Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells , 2016, Immunity.

[20]  S. Lam,et al.  Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis , 2016, Molecular Cancer.

[21]  H. Nishikawa,et al.  Roles of regulatory T cells in cancer immunity. , 2016, International immunology.

[22]  T. Honjo,et al.  Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model , 2016, Proceedings of the National Academy of Sciences.

[23]  Ana C Anderson,et al.  Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. , 2016, Immunity.

[24]  M. Hattori,et al.  Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers , 2016, Nature Medicine.

[25]  Dalya R. Soond,et al.  Corrigendum: Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer , 2016, Nature.

[26]  Jedd D. Wolchok,et al.  PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations , 2016, Science Translational Medicine.

[27]  Deepali V. Sawant,et al.  Interleukin-35 Limits Anti-Tumor Immunity. , 2016, Immunity.

[28]  J. Sakamoto,et al.  Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. , 2015, The Lancet. Haematology.

[29]  T. Fleisher Immune Dysregulation in Human Subjects With Heterozygous Germline Mutations in CTLA4 , 2015, Pediatrics.

[30]  V. Kuchroo,et al.  TIGIT predominantly regulates the immune response via regulatory T cells , 2024, The Journal of clinical investigation.

[31]  S. Iida,et al.  Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients , 2015, Clinical Cancer Research.

[32]  R. Balderas,et al.  Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans , 2015, Proceedings of the National Academy of Sciences.

[33]  C. Meyer,et al.  Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients , 2015, Proceedings of the National Academy of Sciences.

[34]  E. Tartour,et al.  VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors , 2015, The Journal of experimental medicine.

[35]  H. Chi,et al.  Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses , 2015, Nature Immunology.

[36]  D. Sugiyama,et al.  Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals , 2014, Science.

[37]  J. Hackney,et al.  The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. , 2014, Cancer cell.

[38]  Marco Y. Hein,et al.  Continuous T cell receptor signals maintain a functional regulatory T cell pool. , 2014, Immunity.

[39]  A. Schäffer,et al.  Autosomal-dominant immune dysregulation syndrome in humans with CTLA4 mutations , 2014, Nature Medicine.

[40]  C. Benoist,et al.  Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. , 2014, Immunity.

[41]  A. Ohta,et al.  Extracellular Adenosine-Mediated Modulation of Regulatory T Cells , 2014, Front. Immunol..

[42]  J. Svaren,et al.  Bach2 Regulates Homeostasis of Foxp3+ Regulatory T Cells and Protects against Fatal Lung Disease in Mice , 2014, The Journal of Immunology.

[43]  B. Fox,et al.  OX40 is a potent immune-stimulating target in late-stage cancer patients. , 2013, Cancer research.

[44]  J. Karbach,et al.  Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans , 2013, Proceedings of the National Academy of Sciences.

[45]  K. Ladell,et al.  Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3− T cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T cells , 2013, Mucosal Immunology.

[46]  Y. Ohue,et al.  [Anti-CCR4 mAb and regulatory T cells]. , 2013, Gan to kagaku ryoho. Cancer & chemotherapy.

[47]  Jason B. Williams,et al.  Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells , 2013, Science Translational Medicine.

[48]  J. Wolchok,et al.  Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma , 2013, The Journal of experimental medicine.

[49]  G. Dranoff,et al.  Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies , 2013, The Journal of experimental medicine.

[50]  G. Coukos,et al.  Deciphering and reversing tumor immune suppression. , 2013, Immunity.

[51]  J. Bluestone,et al.  Peripherally Induced Tregs – Role in Immune Homeostasis and Autoimmunity , 2013, Front. Immunol..

[52]  F. Marincola,et al.  BACH2 represses effector programmes to stabilize Treg-mediated immune homeostasis - a new target in tumor immunotherapy? , 2013, Journal of Immunotherapy for Cancer.

[53]  A. Korman,et al.  Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells , 2013, Cancer Immunology Research.

[54]  Jenna M. Sullivan,et al.  TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer , 2013, Oncoimmunology.

[55]  E. Tartour,et al.  VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. , 2013, Cancer research.

[56]  L. Fetler,et al.  Regulatory T Cells Increase the Avidity of Primary CD8+ T Cell Responses and Promote Memory , 2012, Science.

[57]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[58]  Antoni Ribas,et al.  Tumor immunotherapy directed at PD-1. , 2012, The New England journal of medicine.

[59]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[60]  A. DeMichele,et al.  CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients , 2012, Science Translational Medicine.

[61]  A. Rudensky,et al.  Regulatory T cells: mechanisms of differentiation and function. , 2012, Annual review of immunology.

[62]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[63]  C. Sautès-Fridman,et al.  The immune contexture in human tumours: impact on clinical outcome , 2012, Nature Reviews Cancer.

[64]  F. Ghiringhelli,et al.  Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer , 2011, Cancer Immunology, Immunotherapy.

[65]  D. Campbell,et al.  Phenotypical and functional specialization of FOXP3+ regulatory T cells , 2011, Nature Reviews Immunology.

[66]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[67]  S. Sakaguchi,et al.  Regulatory T cells in tumor immunity , 2010, International journal of cancer.

[68]  D. Hafler,et al.  FOXP3+ regulatory T cells in the human immune system , 2010, Nature Reviews Immunology.

[69]  D. Getnet,et al.  A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. , 2010, Molecular immunology.

[70]  A. Rudensky,et al.  Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate , 2010, Nature.

[71]  J. Zimmer,et al.  Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer , 2009, PloS one.

[72]  B. Ni,et al.  A Novel Splice Variant of FR4 Predominantly Expressed in CD4+CD25+ Regulatory T Cells# , 2009, Immunological investigations.

[73]  T. Nomura,et al.  Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. , 2009, Immunity.

[74]  L. Boon,et al.  GITR Triggering Induces Expansion of Both Effector and Regulatory CD4+ T Cells In Vivo1 , 2009, The Journal of Immunology.

[75]  Jeffrey M. Wilson,et al.  The A2B Adenosine Receptor Impairs the Maturation and Immunogenicity of Dendritic Cells 1 , 2009, The Journal of Immunology.

[76]  J. Blay,et al.  Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. , 2009, Cancer research.

[77]  T. Eberlein,et al.  Disruption of CCR5-Dependent Homing of Regulatory T Cells Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer1 , 2009, The Journal of Immunology.

[78]  N. Zeps,et al.  Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  C. Hsieh,et al.  Antigen-specific peripheral shaping of the natural regulatory T cell population , 2008, The Journal of experimental medicine.

[80]  T. Nomura,et al.  CTLA-4 Control over Foxp3+ Regulatory T Cell Function , 2008, Science.

[81]  L. Old,et al.  Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling. , 2008, Cancer research.

[82]  A. G. Betz,et al.  Neuropilin-1 Expression on Regulatory T Cells Enhances Their Interactions with Dendritic Cells during Antigen Recognition , 2008, Immunity.

[83]  K. Lam,et al.  ICOS Controls the Pool Size of Effector-Memory and Regulatory T Cells1 , 2008, The Journal of Immunology.

[84]  K. Boyd,et al.  The inhibitory cytokine IL-35 contributes to regulatory T-cell function , 2007, Nature.

[85]  G. Zhu,et al.  Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. , 2007, Cancer research.

[86]  E. Shevach,et al.  Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. , 2007, Blood.

[87]  V. Kuchroo,et al.  Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression , 2007, The Journal of experimental medicine.

[88]  C. Benoist,et al.  Adaptation of TCR Repertoires to Self-Peptides in Regulatory and Nonregulatory CD4+ T Cells1 , 2007, The Journal of Immunology.

[89]  M. Joshi,et al.  Tumor infiltrating Foxp3+ regulatory T‐cells are associated with recurrence in pathologic stage I NSCLC patients , 2006, Cancer.

[90]  Ryuzo Ueda,et al.  CCR4 as a novel molecular target for immunotherapy of cancer , 2006, Cancer science.

[91]  K. Mills,et al.  Suppression of Antitumor Immunity by IL-10 and TGF-β-Producing T Cells Infiltrating the Growing Tumor: Influence of Tumor Environment on the Induction of CD4+ and CD8+ Regulatory T Cells1 , 2006, The Journal of Immunology.

[92]  T. Gingeras,et al.  CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells , 2006, The Journal of experimental medicine.

[93]  W. Selby,et al.  Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells , 2006, The Journal of experimental medicine.

[94]  S. Ziegler FOXP3: of mice and men. , 2006, Annual review of immunology.

[95]  A. Rudensky,et al.  An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires , 2006, Nature Immunology.

[96]  F. Foss Clinical experience with denileukin diftitox (ONTAK). , 2006, Seminars in oncology.

[97]  E. Tartour,et al.  Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers , 2006, Clinical Cancer Research.

[98]  V. Kuchroo,et al.  The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity , 2005, Nature Immunology.

[99]  R. Schreiber,et al.  IFN-γ Controls the Generation/Activation of CD4+CD25+ Regulatory T Cells in Antitumor Immune Response1 , 2005, The Journal of Immunology.

[100]  R. Schreiber,et al.  Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells , 2005, The Journal of experimental medicine.

[101]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[102]  G. Freeman,et al.  CD4 CD25 T Regulatory Cells Dependent on ICOS Promote Regulation of Effector Cells in the Prediabetic Lesion , 2004 .

[103]  C. Uyttenhove,et al.  Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase , 2003, Nature Medicine.

[104]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[105]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2003 .

[106]  T. Tüting,et al.  Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. , 2001, Cancer research.

[107]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[108]  J. Shimizu,et al.  Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. , 1999, Journal of immunology.

[109]  T. Fujita,et al.  Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. , 1999, Cancer research.

[110]  M. Toda,et al.  Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. , 1998, International immunology.

[111]  Ethan M. Shevach,et al.  CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production , 1998, The Journal of experimental medicine.

[112]  A. Enk,et al.  Induction of tolerance by IL-10-treated dendritic cells. , 1997, Journal of immunology.

[113]  T. Strom,et al.  Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. , 1997, Immunity.

[114]  P. ten Dijke,et al.  Targeting TGF-β Signaling in Cancer. , 2017, Trends in cancer.

[115]  H. Nishikawa,et al.  Regulatory T Cells: Molecular and Cellular Basis for Immunoregulation. , 2017, Current topics in microbiology and immunology.

[116]  C. Punt,et al.  Clinical Cancer esearch cer Therapy : Clinical dritic Cell Vaccination in Combination with Anti-CD 25 oclonal Antibody Treatment : A Phase I / II Study in R astatic Melanoma Patients , 2010 .

[117]  P. Stumbles,et al.  The role of dendritic cells and regulatory T cells in the regulation of allergic asthma. , 2010, Pharmacology & therapeutics.

[118]  R. Schreiber,et al.  IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. , 2005, Journal of immunology.

[119]  H. Ochs,et al.  The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 , 2001, Nature Genetics.