1932

Abstract

The immune system has evolved complex effector mechanisms to protect the host against a diversity of pathogenic organisms and regulatory adaptations that can curtail pathological sequelae of inflammatory events, prevent autoimmunity, and assist in tissue repair. Cancers, by virtue of their local manifestations of tissue dysfunction and destruction, inflammation, and genomic instability, can evoke these protective mechanisms, which support the progression of tumors and prevent their immune eradication. Central to these processes is a subset of CD4+ T cells, known as regulatory T (Treg) cells, that express the X chromosome–linked transcription factor FOXP3. In addition to their critical role in controlling autoimmunity and suppressing inflammatory responses in diverse biological settings, Treg cells are ubiquitously present in the tumor microenvironment where they promote tumor development and progression by dampening antitumor immune responses. Furthermore, Treg cells can directly support the survival of transformed cells through the elaboration of growth factors and interacting with accessory cells in tumors such as fibroblasts and endothelial cells. Current insights into the biology of tumor-associated Treg cells have opened up opportunities for their selective targeting in cancer, with the goal of alleviating their suppression of antitumor immune responses while maintaining overall immune homeostasis.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030419-033428
2020-03-04
2024-04-17
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/4/1/annurev-cancerbio-030419-033428.html?itemId=/content/journals/10.1146/annurev-cancerbio-030419-033428&mimeType=html&fmt=ahah

Literature Cited

  1. Ahern E, Harjunpaa H, Barkauskas D, Allen S, Takeda K et al. 2017. Co-administration of RANKL and CTLA4 antibodies enhances lymphocyte-mediated antitumor immunity in mice. Clin. Cancer Res. 23:5789–801
    [Google Scholar]
  2. Ahern E, Smyth MJ, Dougall WC, Teng MWL 2018. Roles of the RANKL-RANK axis in antitumour immunity—implications for therapy. Nat. Rev. Clin. Oncol. 15:676–93
    [Google Scholar]
  3. Ahmadzadeh M, Pasetto A, Jia L, Deniger DC, Stevanovic S et al. 2019. Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity. Sci. Immunol. 4:eaao4310
    [Google Scholar]
  4. Aida K, Miyakawa R, Suzuki K, Narumi K, Udagawa T et al. 2014. Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer. Cancer Sci 105:159–67
    [Google Scholar]
  5. Anderson AC, Joller N, Kuchroo VK 2016. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44:989–1004
    [Google Scholar]
  6. Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L et al. 2017. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25:1282–93.e7
    [Google Scholar]
  7. Antonioli L, Blandizzi C, Pacher P, Hasko G 2013. Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer 13:842–57
    [Google Scholar]
  8. Araujo L, Khim P, Mkhikian H, Mortales CL, Demetriou M 2017. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife 6:e21330
    [Google Scholar]
  9. Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R et al. 2018. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33:649–63.e4
    [Google Scholar]
  10. Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L et al. 2017. Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46:577–86
    [Google Scholar]
  11. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S et al. 2015. A distinct function of regulatory T cells in tissue protection. Cell 162:1078–89
    [Google Scholar]
  12. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle A 2016. Rationale for anti-OX40 cancer immunotherapy. Eur. J. Cancer 52:50–66
    [Google Scholar]
  13. Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C et al. 2018. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174:1293–308.e36
    [Google Scholar]
  14. Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA et al. 2009. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 183:2475–83
    [Google Scholar]
  15. Bayry J, Tchilian EZ, Davies MN, Forbes EK, Draper SJ et al. 2008. In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination. PNAS 105:10221–26
    [Google Scholar]
  16. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ et al. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. . Genet 27:20–21
    [Google Scholar]
  17. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S et al. 2014. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20:1327–33
    [Google Scholar]
  18. Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C et al. 2009. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J. Clin. Investig. 119:3311–21
    [Google Scholar]
  19. Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY 2013. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J. Exp. Med. 210:2435–66
    [Google Scholar]
  20. Bour-Jordan H, Bluestone JA. 2009. Regulating the regulators: Costimulatory signals control the homeostasis and function of regulatory T cells. Immunol. Rev. 229:41–66
    [Google Scholar]
  21. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB et al. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27:68–73
    [Google Scholar]
  22. Buck MD, Sowell RT, Kaech SM, Pearce EL 2017. Metabolic instruction of immunity. Cell 169:570–86
    [Google Scholar]
  23. Cao X, Cai SF, Fehniger TA, Song J, Collins LI et al. 2007. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27:635–46
    [Google Scholar]
  24. Chai JG. 2011. Cancer vaccination reprograms regulatory T cells into helper CD4 T cells to promote antitumor CD8 T-cell responses. Immunotherapy 3:601–4
    [Google Scholar]
  25. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C et al. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Investig. 106:R75–81
    [Google Scholar]
  26. Chen W, Jin W, Hardegen N, Lei KJ, Li L et al. 2003. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. . Med 198:1875–86
    [Google Scholar]
  27. Chensue SW, Lukacs NW, Yang TY, Shang X, Frait KA et al. 2001. Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J. Exp. Med. 193:573–84
    [Google Scholar]
  28. Cheung LS, Fu J, Kumar P, Kumar A, Urbanowski ME et al. 2019. Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti-PD-1 in melanoma. PNAS 116:3100–5
    [Google Scholar]
  29. Chinen T, Kannan AK, Levine AG, Fan X, Klein U et al. 2016. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17:1322–33
    [Google Scholar]
  30. Chopra M, Biehl M, Steinfatt T, Brandl A, Kums J et al. 2016. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. J. Exp. Med. 213:1881–900
    [Google Scholar]
  31. Chu GC, Chung LW. 2014. RANK-mediated signaling network and cancer metastasis. Cancer Metastasis Rev 33:497–509
    [Google Scholar]
  32. Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D et al. 2010. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLOS ONE 5:e10436
    [Google Scholar]
  33. Colombo MP, Piconese S. 2007. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat. Rev. Cancer 7:880–87
    [Google Scholar]
  34. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P et al. 2004. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10:942–49
    [Google Scholar]
  35. Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A et al. 2007. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25 into CD25+ T regulatory cells. Blood 109:2871–77
    [Google Scholar]
  36. Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L et al. 2013. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 73:7189–98
    [Google Scholar]
  37. Davies MN, Bayry J, Tchilian EZ, Vani J, Shaila MS et al. 2009. Toward the discovery of vaccine adjuvants: coupling in silico screening and in vitro analysis of antagonist binding to human and mouse CCR4 receptors. PLOS ONE 4:e8084
    [Google Scholar]
  38. De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V et al. 2016. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45:1135–47
    [Google Scholar]
  39. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A et al. 2007. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204:1257–65
    [Google Scholar]
  40. Demaria S, Formenti SC. 2013. Radiotherapy effects on anti-tumor immunity: implications for cancer treatment. Front. Oncol. 3:128
    [Google Scholar]
  41. Dimeloe S, Frick C, Fischer M, Gubser PM, Razik L et al. 2014. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur. J. Immunol. 44:3614–20
    [Google Scholar]
  42. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F et al. 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8:793–800
    [Google Scholar]
  43. Dunn GP, Old LJ, Schreiber RD 2004. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–48
    [Google Scholar]
  44. Ehrlich P. 1906. The Collected Papers of Paul Ehrlich, Vol. 2, Immunology and Cancer Research F Himmelweit New York: Pergamon
    [Google Scholar]
  45. Faget J, Biota C, Bachelot T, Gobert M, Treilleux I et al. 2011. Early detection of tumor cells by innate immune cells leads to Treg recruitment through CCL22 production by tumor cells. Cancer Res 71:6143–52
    [Google Scholar]
  46. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR et al. 2006. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176:6752–61
    [Google Scholar]
  47. Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G et al. 2014. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 1158:4749–63
    [Google Scholar]
  48. Ferrara R, Susini S, Marabelle A 2018. Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers—letter. Clin. Cancer Res. 25:3468
    [Google Scholar]
  49. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J et al. 2007. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–19
    [Google Scholar]
  50. Fontenot JD, Gavin MA, Rudensky AY 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4:330–36
    [Google Scholar]
  51. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:1142–51
    [Google Scholar]
  52. Formenti SC, Demaria S. 2009. Systemic effects of local radiotherapy. Lancet Oncol 10:718–26
    [Google Scholar]
  53. Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E et al. 2018. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24:1845–51
    [Google Scholar]
  54. Fu J, Xu D, Liu Z, Shi M, Zhao P et al. 2007. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–39
    [Google Scholar]
  55. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G 2012. The secret ally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discov. 11:215–33
    [Google Scholar]
  56. Gasteiger G, Hemmers S, Firth MA, Le Floc'h A, Huse M et al. 2013. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J. Exp. Med. 210:1167–78
    [Google Scholar]
  57. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D et al. 2004. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur. J. Immunol. 34:336–44
    [Google Scholar]
  58. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R 2011. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin. Cancer Res. 17:6985–91
    [Google Scholar]
  59. Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP et al. 2010. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468:103–7
    [Google Scholar]
  60. Green JA, Arpaia N, Schizas M, Dobrin A, Rudensky AY 2017. A nonimmune function of T cells in promoting lung tumor progression. J. Exp. Med. 214:3565–75
    [Google Scholar]
  61. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ 2004. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601
    [Google Scholar]
  62. Ha D, Tanaka A, Kibayashi T, Tanemura A, Sugiyama D et al. 2019. Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody. PNAS 116:609–18
    [Google Scholar]
  63. Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646–74
    [Google Scholar]
  64. Hori S, Nomura T, Sakaguchi S 2003. Control of regulatory T cell development by the transcription factor Foxp3. . Science 299:1057–61
    [Google Scholar]
  65. Howie D, Cobbold SP, Adams E, Ten Bokum A, Necula AS et al. 2017. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight 2:e89160
    [Google Scholar]
  66. Hoy AJ, Balaban S, Saunders DN 2017. Adipocyte-tumor cell metabolic crosstalk in breast cancer. Trends Mol. Med. 23:381–92
    [Google Scholar]
  67. Hui E, Cheung J, Zhu J, Su X, Taylor MJ et al. 2017. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:1428–33
    [Google Scholar]
  68. Huss DJ, Pellerin AF, Collette BP, Kannan AK, Peng L et al. 2016. Anti-CD25 monoclonal antibody Fc variants differentially impact Treg cells and immune homeostasis. Immunology 148:276–86
    [Google Scholar]
  69. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N 2002. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. PNAS 99:12293–97
    [Google Scholar]
  70. Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM et al. 2010. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin. Cancer Res. 16:5067–78
    [Google Scholar]
  71. Josefowicz SZ, Lu LF, Rudensky AY 2012. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30:531–64
    [Google Scholar]
  72. Josefowicz SZ, Rudensky A. 2009. Control of regulatory T cell lineage commitment and maintenance. Immunity 30:616–25
    [Google Scholar]
  73. Kalliolias GD, Ivashkiv LB. 2016. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12:149–62
    [Google Scholar]
  74. Khattri R, Cox T, Yasayko SA, Ramsdell F 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4:337–42
    [Google Scholar]
  75. Kim IK, Kim BS, Koh CH, Seok JW, Park JS et al. 2015. Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells. Nat. Med. 21:1010–17
    [Google Scholar]
  76. Kim JM, Rasmussen JP, Rudensky AY 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191–97
    [Google Scholar]
  77. Kleinfeld AM, Okada C. 2005. Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing. J. Lipid Res. 46:1983–90
    [Google Scholar]
  78. Klotz L, Burgdorf S, Dani I, Saijo K, Flossdorf J et al. 2009. The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med. 206:2079–89
    [Google Scholar]
  79. Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G et al. 2015. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal 8:ra97
    [Google Scholar]
  80. Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K et al. 2005. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J. Exp. Med. 202:885–91
    [Google Scholar]
  81. Komatsu N, Hori S. 2007. Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras. PNAS 104:8959–64
    [Google Scholar]
  82. Kurose K, Ohue Y, Wada H, Iida S, Ishida T et al. 2015. Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. Clin. Cancer Res. 21:4327–36
    [Google Scholar]
  83. Levine AG, Arvey A, Jin W, Rudensky AY 2014. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15:1070–78
    [Google Scholar]
  84. Leyland R, Watkins A, Mulgrew KA, Holoweckyj N, Bamber L et al. 2017. A novel murine GITR ligand fusion protein induces antitumor activity as a monotherapy that is further enhanced in combination with an OX40 agonist. Clin. Cancer Res. 23:3416–27
    [Google Scholar]
  85. Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q 2010. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood 116:210–17
    [Google Scholar]
  86. Liang B, Workman C, Lee J, Chew C, Dale BM et al. 2008. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J. Immunol. 180:5916–26
    [Google Scholar]
  87. Liu X, Mo W, Ye J, Li L, Zhang Y et al. 2018. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat. Commun. 9:249
    [Google Scholar]
  88. Lochner M, Berod L, Sparwasser T 2015. Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36:81–91
    [Google Scholar]
  89. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H 2005. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–68
    [Google Scholar]
  90. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE et al. 2016. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253–57
    [Google Scholar]
  91. Magnuson AM, Kiner E, Ergun A, Park JS, Asinovski N et al. 2018. Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. PNAS 115:E10672–81
    [Google Scholar]
  92. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y et al. 2014. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15:473–81
    [Google Scholar]
  93. Mahne AE, Mauze S, Joyce-Shaikh B, Xia J, Bowman EP et al. 2017. Dual roles for regulatory T-cell depletion and costimulatory signaling in agonistic GITR targeting for tumor immunotherapy. Cancer Res 77:1108–18
    [Google Scholar]
  94. Mahnke K, Schonfeld K, Fondel S, Ring S, Karakhanova S et al. 2007. Depletion of CD4+CD25+ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro. Int. J. Cancer 120:2723–33
    [Google Scholar]
  95. Maj T, Wang W, Crespo J, Zhang H, Wang W et al. 2017. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18:1332–41
    [Google Scholar]
  96. Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC et al. 2013. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Investig. 123:2447–63
    [Google Scholar]
  97. Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA et al. 2016. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22:2908–18
    [Google Scholar]
  98. McHugh RS, Shevach EM. 2002. Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J. Immunol. 168:5979–83
    [Google Scholar]
  99. McIntire KR, Sell S, Miller JF 1964. Pathogenesis of the post-neonatal thymectomy wasting syndrome. Nature 204:151–55
    [Google Scholar]
  100. Munn DH, Mellor AL. 2016. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 37:193–207
    [Google Scholar]
  101. Muroyama Y, Nirschl TR, Kochel CM, Lopez-Bujanda Z, Theodros D et al. 2017. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol. Res. 5:992–1004
    [Google Scholar]
  102. Nagarsheth N, Wicha MS, Zou W 2017. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17:9559–72
    [Google Scholar]
  103. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G et al. 2001. Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 98:2736–44
    [Google Scholar]
  104. Nishimura H, Nose M, Hiai H, Minato N, Honjo T 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–51
    [Google Scholar]
  105. Nishizuka Y, Sakakura T. 1969. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166:753–55
    [Google Scholar]
  106. Olsen E, Duvic M, Frankel A, Kim Y, Martin A et al. 2001. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J. Clin. Oncol. 19:376–88
    [Google Scholar]
  107. Onda M, Kobayashi K, Pastan I 2019. Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity. PNAS 116:104575–82
    [Google Scholar]
  108. Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E et al. 2018. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. PNAS 115:E6546–55
    [Google Scholar]
  109. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ 2007. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8:1353–62
    [Google Scholar]
  110. Paterson AM, Lovitch SB, Sage PT, Juneja VR, Lee Y et al. 2015. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J. Exp. Med. 212:1603–21
    [Google Scholar]
  111. Pearce EL, Poffenberger MC, Chang CH, Jones RG 2013. Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454
    [Google Scholar]
  112. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP 2009. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206:1717–25
    [Google Scholar]
  113. Pere H, Montier Y, Bayry J, Quintin-Colonna F, Merillon N et al. 2011. A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Blood 118:4853–62
    [Google Scholar]
  114. Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB et al. 2006. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107:2866–72
    [Google Scholar]
  115. Piconese S, Valzasina B, Colombo MP 2008. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J. Exp. Med. 205:825–39
    [Google Scholar]
  116. Plitas G, Konopacki C, Wu K, Bos PD, Morrow M et al. 2016. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 45:1122–34
    [Google Scholar]
  117. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C et al. 2011. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332:600–3
    [Google Scholar]
  118. Rech AJ, Mick R, Martin S, Recio A, Aqui NA et al. 2012. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4:134ra62
    [Google Scholar]
  119. Ren L, Yu Y, Wang L, Zhu Z, Lu R, Yao Z 2016. Hypoxia-induced CCL28 promotes recruitment of regulatory T cells and tumor growth in liver cancer. Oncotarget 7:75763–73
    [Google Scholar]
  120. Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M et al. 2016. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 17:1599–611
    [Google Scholar]
  121. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J et al. 2011. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New Engl. J. Med. 364:2517–26
    [Google Scholar]
  122. Rohrig F, Schulze A. 2016. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16:732–49
    [Google Scholar]
  123. Rollinghoff M, Starzinski-Powitz A, Pfizenmaier K, Wagner H 1977. Cyclophosphamide-sensitive T lymphocytes suppress the in vivo generation of antigen-specific cytotoxic T lymphocytes. J. Exp. Med. 145:455–59
    [Google Scholar]
  124. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C et al. 2015. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. PNAS 112:6140–45
    [Google Scholar]
  125. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L et al. 2008. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28:546–58
    [Google Scholar]
  126. Rudensky AY. 2011. Regulatory T cells and Foxp3. Immunol. Rev. 241:260–68
    [Google Scholar]
  127. Sage PT, Francisco LM, Carman CV, Sharpe AH 2013. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 14:152–61
    [Google Scholar]
  128. Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D et al. 2016. Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat. Med. 22:679–84
    [Google Scholar]
  129. Sakaguchi S. 2004. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22:531–62
    [Google Scholar]
  130. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25): Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151–64
    [Google Scholar]
  131. Sawant DV, Yano H, Chikina M, Zhang Q, Liao M et al. 2019. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat. Immunol. 20:724–35
    [Google Scholar]
  132. Schaer DA, Murphy JT, Wolchok JD 2012. Modulation of GITR for cancer immunotherapy. Curr. Opin. Immunol. 24:217–24
    [Google Scholar]
  133. Scurr M, Pembroke T, Bloom A, Roberts D, Thomson A et al. 2017. Effect of modified vaccinia Ankara-5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: a randomized clinical trial. JAMA Oncol 3:e172579
    [Google Scholar]
  134. Setoguchi R, Hori S, Takahashi T, Sakaguchi S 2005. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201:723–35
    [Google Scholar]
  135. Sevko A, Sade-Feldman M, Kanterman J, Michels T, Falk CS et al. 2013. Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma. J. Investig. Dermatol. 133:1610–19
    [Google Scholar]
  136. Sharma MD, Hou DY, Liu Y, Koni PA, Metz R et al. 2009. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113:6102–11
    [Google Scholar]
  137. Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB et al. 2015. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci. Adv. 1:e1500845
    [Google Scholar]
  138. Shen Z, Zhou S, Wang Y, Li RL, Zhong C et al. 2010. Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer. J. Cancer Res. Clin. Oncol. 136:1585–95
    [Google Scholar]
  139. Shimizu J, Yamazaki S, Sakaguchi S 1999. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163:5211–18
    [Google Scholar]
  140. Shrimali RK, Ahmad S, Verma V, Zeng P, Ananth S et al. 2017. Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis. Cancer Immunol. Res. 5:755–66
    [Google Scholar]
  141. Siu LL, Steeghs N, Meniawy T, Joerger M, Spratlin JL et al. 2017. Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors. J. Clin. Oncol. 35:104
    [Google Scholar]
  142. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ et al. 2011. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–53
    [Google Scholar]
  143. Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y et al. 2014. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLOS ONE 9:e87705
    [Google Scholar]
  144. Torrey H, Butterworth J, Mera T, Okubo Y, Wang L et al. 2017. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci. Signal. 10:eaaf8608
    [Google Scholar]
  145. Vence L, Palucka AK, Fay JW, Ito T, Liu YJ et al. 2007. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. PNAS 104:20884–89
    [Google Scholar]
  146. Vignali DA, Collison LW, Workman CJ 2008. How regulatory T cells work. Nat. Rev. Immunol. 8:7523–32
    [Google Scholar]
  147. Villarreal DO, L'Huillier A, Armington S, Mottershead C, Filippova EV et al. 2018. Targeting CCR8 induces protective antitumor immunity and enhances vaccine-induced responses in colon cancer. Cancer Res 78:5340–48
    [Google Scholar]
  148. von Boehmer H. 2005. Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6:338–44
    [Google Scholar]
  149. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M et al. 2003. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25 T cells. J. Clin. Investig. 112:1437–43
    [Google Scholar]
  150. Ward ST, Li KK, Hepburn E, Weston CJ, Curbishley SM et al. 2015. The effects of CCR5 inhibition on regulatory T-cell recruitment to colorectal cancer. Br. J. Cancer 112:319–28
    [Google Scholar]
  151. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL et al. 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27:18–20
    [Google Scholar]
  152. Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC et al. 2018. A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti–PD-(L)1 and anti–CTLA-4 in preclinical models. Cancer Immunol. Res. 6:1136–49
    [Google Scholar]
  153. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M et al. 2008. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–75
    [Google Scholar]
  154. Wu SP, Liao RQ, Tu HY, Wang WJ, Dong ZY et al. 2018. Stromal PD-L1-positive regulatory T cells and PD-1-positive CD8-positive T cells define the response of different subsets of non-small cell lung cancer to PD-1/PD-L1 blockade immunotherapy. J. Thorac. Oncol. 13:521–32
    [Google Scholar]
  155. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY 2010. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:7282808–12
    [Google Scholar]
  156. Zhou G, Levitsky HI. 2007. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J. Immunol. 178:2155–62
    [Google Scholar]
  157. Zou W. 2006. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6:295–307
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030419-033428
Loading
/content/journals/10.1146/annurev-cancerbio-030419-033428
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error