Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Togashi, Y. & Nishikawa, H. Regulatory T cells: molecular and cellular basis for immunoregulation. Curr. Top. Microbiol. Immunol. 410, 3–27 (2017).
Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).
Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11, 7–13 (2010).
Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).
Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).
Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).
Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 2011).
Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).
Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).
Williams, J. B. et al. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J. Exp. Med. 214, 381–400 (2017).
Spranger, S. et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl Med. 5, 200ra116 (2013).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl Med. 8, 328rv4 (2016).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Onizuka, S. et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 59, 3128–3133 (1999).
Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).
Overacre-Delgoffe, A. E. et al. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 169, 1130–1141 (2017).
Sarris, M., Andersen, K. G., Randow, F., Mayr, L. & Betz, A. G. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 28, 402–413 (2008).
Getnet, D. et al. A role for the transcription factor Helios in human CD4+CD25+ regulatory T cells. Mol. Immunol. 47, 1595–1600 (2010).
Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).
Walker, M. R., Carson, B. D., Nepom, G. T., Ziegler, S. F. & Buckner, J. H. De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25− cells. Proc. Natl Acad. Sci. USA 102, 4103–4108 (2005).
Tran, D. Q., Ramsey, H. & Shevach, E. M. 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. Blood 110, 2983–2990 (2007).
Ellis, G. I., Reneer, M. C., Vélez-Ortega, A. C., McCool, A. & Martí, F. Generation of induced regulatory T cells from primary human naïve and memory T cells. J. Vis. Exp. 62, 3738 (2012).
Hsu, P. et al. IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1. J. Immunol. 195, 3665–3674 (2015).
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).
Weissler, K. A. & Caton, A. J. The role of T cell receptor recognition of peptide:MHC complexes in the formation and activity of Foxp3+ regulatory T cells. Immunol. Rev. 259, 11–22 (2014).
Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100–111 (2008).
Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12, 180–190 (2012).
Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).
Hsieh, C. S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).
Burchill, M. A. et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28, 112–121 (2008).
Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R. & Farrar, M. A. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290 (2007).
Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).
Li, X., Liang, Y., LeBlanc, M., Benner, C. & Zheng, Y. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158, 734–748 (2014).
Tai, X. et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38, 1116–1128 (2013).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Zhang, R. et al. An obligate cell-intrinsic function for CD28 in Tregs. J. Clin. Invest. 123, 580–593 (2013).
Franckaert, D. et al. Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3+ and Foxp3− T cells. Immunol. Cell Biol. 93, 417–423 (2015).
Ouyang, W. et al. Novel Foxo1-dependent transcriptional programs control Treg cell function. Nature 491, 554–559 (2012).
Samstein, R. M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153–166 (2012).
Harada, Y. et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J. Exp. Med. 207, 1381–1391 (2010).
Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLOS Biol. 5, e38 (2007).
Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799 (2012).
Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).
Morikawa, H. et al. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl Acad. Sci. USA 111, 5289–5294 (2014).
Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).
Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).
Mazzucchelli, R. & Durum, S. K. Interleukin-7 receptor expression: intelligent design. Nat. Rev. Immunol. 7, 144–154 (2007).
Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).
Takahashi, T. 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. Int. Immunol. 10, 1969–1980 (1998).
Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).
Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).
Perez, V. L. et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6, 411–417 (1997).
Steinbrink, K., Wölfl, M., Jonuleit, H., Knop, J. & Enk, A. H. Induction of tolerance by IL-10-treated dendritic cells. J. Immunol. 159, 4772–4780 (1997).
Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T cell function. Nature 450, 566–569 (2007).
Turnis, M. E. et al. Interleukin-35 limits anti-tumor immunity. Immunity 44, 316–329 (2016).
Jarnicki, A. G., Lysaght, J., Todryk, S. & Mills, K. H. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J. Immunol. 177, 896–904 (2006).
Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).
Wilson, J. M. et al. The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J. Immunol. 182, 4616–4623 (2009).
Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).
Schubert, D. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20, 1410–1416 (2014).
Kuehn, H. S. et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345, 1623–1627 (2014).
Birzele, F. et al. Next-generation insights into regulatory T cells: expression profiling and FoxP3 occupancy in human. Nucleic Acids Res. 39, 7946–7960 (2011).
Walker, L. S. & Sansom, D. M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 11, 852–863 (2011).
Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).
Tada, Y. et al. Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8. J. Immunother. Cancer 6, 106 (2018).
Saito, T. et al. Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat. Med. 22, 679–684 (2016).
Fridman, W. H., Pagès, F., Sautès-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).
Kryczek, I. et al. Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma. Oncoimmunology 5, e1105430 (2016).
Kryczek, I. et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J. Immunol. 186, 4388–4395 (2011).
Kryczek, I. et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res. 69, 3995–4000 (2009).
Colbeck, E. J. et al. Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction. Cancer Immunol. Res. 5, 1005–1015 (2017).
Hindley, J. P. et al. T cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T cell depletion. Cancer Res. 72, 5473–5482 (2012).
Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl Acad. Sci. USA 110, 17945–17950 (2013).
De Simone, M. et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45, 1135–1147 (2016).
Maj, T. et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18, 1332–1341 (2017).
Togashi, Y. & Nishikawa, H. Suppression from beyond the grave. Nat. Immunol. 18, 1285–1286 (2017).
Nishikawa, H. et al. Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells. J. Exp. Med. 201, 681–686 (2005).
Ghiringhelli, F. et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J. Exp. Med. 202, 919–929 (2005).
Hindley, J. P. et al. Analysis of the T cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res. 71, 736–746 (2011).
Sainz-Perez, A., Lim, A., Lemercier, B. & Leclerc, C. The T cell receptor repertoire of tumor-infiltrating regulatory T lymphocytes is skewed toward public sequences. Cancer Res. 72, 3557–3569 (2012).
Nishikawa, H. et al. IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. J. Immunol. 175, 4433–4440 (2005).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).
Wei, S. et al. Interleukin-2 administration alters the CD4+FOXP3+ T cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res. 67, 7487–7494 (2007).
Tan, M. C. et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 182, 1746–1755 (2009).
Zou, L. et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 64, 8451–8455 (2004).
Hoelzinger, D. B. et al. Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses. J. Immunol. 184, 6833–6842 (2010).
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).
Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).
Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).
Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).
Pace, L. et al. Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 338, 532–536 (2012).
Maeda, Y. et al. Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals. Science 346, 1536–1540 (2014).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Larkin, J., Hodi, F. S. & Wolchok, J. D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270–1271 (2015).
Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).
Togashi, Y. et al. Clinicopathological, genomic and immunological features of hyperprogressive disease during PD-1 blockade in gastric cancer patients. J. Clin. Oncol. 36, 4106 (2018).
Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33, 649–663 (2018).
Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013).
Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).
Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).
Sharma, A. et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3+regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-3740 (2018).
Yokosuka, T. et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209, 1201–1217 (2012).
Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).
Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).
Levine, A. G., Arvey, A., Jin, W. & Rudensky, A. Y. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15, 1070–1078 (2014).
Zhang, B., Chikuma, S., Hori, S., Fagarasan, S. & Honjo, T. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc. Natl Acad. Sci. USA 113, 8490–8495 (2016).
Lowther, D. E. et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1, e85935 (2016).
Park, H. J. et al. PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. J. Immunol. 194, 5801–5811 (2015).
Stathopoulou, C. et al. PD-1 inhibitory receptor downregulates asparaginyl endopeptidase and maintains Foxp3 transcription factor stability in induced regulatory T cells. Immunity 49, 247–263 (2018).
Asano, T. et al. PD-1 modulates regulatory T cell homeostasis during low-dose interleukin-2 therapy. Blood 129, 2186–2197 (2017).
Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Voron, T. et al. Control of the immune response by pro-angiogenic factors. Front. Oncol. 4, 70 (2014).
Metelli, A. et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. J. Hematol. Oncol. 11, 24 (2018).
Litzinger, M. T. et al. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T cell immunity. Blood 110, 3192–3201 (2007).
Dannull, J. et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J. Clin. Invest. 115, 3623–3633 (2005).
Mahnke, K. et al. 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, 2723–2733 (2007).
Rech, A. J. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl Med. 4, 134ra62 (2012).
Jacobs, J. F. et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin. Cancer Res. 16, 5067–5078 (2010).
Abbas, A. K., Trotta, E. R., Simeonov, D., Marson, A. & Bluestone, J. A. Revisiting IL-2: biology and therapeutic prospects. Sci. Immunol. 3, eaat1482 (2018).
Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).
Kurose, K. et al. 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, 4327–4336 (2015).
Yamamoto, N. et al. Anti-CC-chemokine receptor 4 (CCR4) antibody mogamulizumab (Moga) and nivolumab (Nivo) combination phase I study in patents with advanced or metastatic solid tumor. Ann. Oncol. 28, v605–v649 (2017).
Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).
Griseri, T., Asquith, M., Thompson, C. & Powrie, F. OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699–709 (2010).
Piconese, S., Valzasina, B. & Colombo, M. P. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J. Exp. Med. 205, 825–839 (2008).
Valzasina, B. et al. Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 105, 2845–2851 (2005).
Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189–7198 (2013).
Hamid, O. et al. First in human (FIH) study of an OX40 agonist monoclonal antibody (mAb) PF-04518600 (PF-8600) in adult patients (pts) with select advanced solid tumors: preliminary safety and pharmacokinetic (PK)/pharmacodynamic results. J. Clin. Oncol. 34, 3079 (2016).
Geva, R. et al. First-in-human phase 1 study of MK-1248, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody, as monotherapy or in combination with pembrolizumab in patients with advanced solid tumors. J. Clin. Oncol. 36, 3029 (2018).
Nagase, H. et al. ICOS+ Foxp3+ TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori. Int. J. Cancer 140, 686–695 (2017).
Burris, H. A. et al. Phase 1 safety of ICOS agonist antibody JTX-2011 alone and with nivolumab (nivo) in advanced solid tumors; predicted versus observed pharmacokinetics (PK) in ICONIC. J. Clin. Oncol. 35, 3033 (2017).
Yap, T. A. et al. ICONIC: biologic and clinical activity of first in class ICOS agonist antibody JTX-2011+/- nivolumab (nivo) in patients (pts) with advanced cancers. J. Clin. Oncol. 36, 3000 (2018).
Ahmad, S. et al. Differential PI3Kdelta signaling in CD4+ T cell subsets enables selective targeting of T regulatory cells to enhance cancer immunotherapy. Cancer Res. 77, 1892–1904 (2017).
Ali, K. et al. Inactivation of PI(3)K p110δ breaks regulatory T cell-mediated immune tolerance to cancer. Nature 510, 407–411 (2014).
Vahl, J. C. et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41, 722–736 (2014).
Imagawa, J. 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. Lancet Haematol. 2, e528–e535 (2015).
Speeckaert, R. et al. Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients. Eur. J. Cancer 48, 2004–2011 (2012).
Smith, C. et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2, 722–735 (2012).
Holmgaard, R. B. et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 13, 412–424 (2015).
Brochez, L., Chevolet, I. & Kruse, V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur. J. Cancer 76, 167–182 (2017).
Beatty, G. L. et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin. Cancer Res. 23, 3269–3276 (2017).
Mitchell, T. C. et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol. 36, 3223–3230 (2018).
Long, G. V. et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J. Clin. Oncol. 36 (Suppl), 108 (2018).
Terme, M. et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).
Roland, C. L. et al. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLOS ONE 4, e7669 (2009).
Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).
Herbst, R. S. et al. A phase 1 study of ramucirumab (R) plus pembrolizumab (P) in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC): phase 1a results. J. Clin. Oncol. 34, 3056 (2016).
Chau, I. et al. Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: a multi-disease phase I study. J. Clin. Oncol. 35, 4046 (2017).
Wallin, J. J. et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T cell migration in metastatic renal cell carcinoma. Nat. Commun. 7, 12624 (2016).
Motzer, R. J. et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab versus sunitinib in untreated metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 36, 578 (2018).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).
Desar, I. M. et al. Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients. Int. J. Cancer 129, 507–512 (2011).
Principe, D. R. et al. TGF-β: duality of function between tumor prevention and carcinogenesis. J. Natl Cancer Inst. 106, djt369 (2014).
Oh, S. A. et al. Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance. Proc. Natl Acad. Sci. USA 114, E7536–E7544 (2017).
Holmgaard, R. B. 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. J. Immunother. Cancer 6, 47 (2018).
Lan, Y. et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci. Transl Med. 10, eaan5488 (2018).
Strauss, J. et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin. Cancer Res. 24, 1287–1295 (2018).
Kang, Y.-K. et al. M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated recurrent or refractory gastric cancer: preliminary results from a phase I trial. J. Clin. Oncol. 36, 100 (2018).
Proia, D. A. & Kaufmann, G. F. Targeting heat-shock protein 90 (HSP90) as a complementary strategy to immune checkpoint blockade for cancer therapy. Cancer Immunol. Res. 3, 583–589 (2015).
Zininga, T., Ramatsui, L. & Shonhai, A. Heat shock proteins as immunomodulants. Molecules 23, 2846 (2018).
Wachstein, J. et al. HSP70 enhances immunosuppressive function of CD4+CD25+FoxP3+ T regulatory cells and cytotoxicity in CD4+CD25− T cells. PLOS ONE 7, e51747 (2012).
Rao, A. et al. Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells. Cancer Res. 72, 3196–3206 (2012).
Mbofung, R. M. et al. HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nat. Commun. 8, 451 (2017).
Jones, S. F. et al. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. Invest. New Drugs 33, 1100–1107 (2015).
Soria, J.-C. et al. Phase I clinical and pharmacologic study of the focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with advanced solid tumors. J. Clin. Oncol. 30, 3000 (2012).
Bueno, R. et al. Effect of FAK inhibitor defactinib on tumor immune changes and tumor reductions in a phase II window of opportunity study in malignant pleural mesothelioma (MPM). J. Clin. Oncol. 35, 8555 (2017).
Scurr, M. et al. Low-dose cyclophosphamide induces antitumor T-cell responses, which associate with survival in metastatic colorectal cancer. Clin. Cancer Res. 23, 6771–6780 (2017).
Scurr, M. et al. 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 (2017).
Walter, S. et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat. Med. 18, 1254–1261 (2012).
Rini, B. I. et al. 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, 1599–1611 (2016).
Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).
Galluzzi, L., Senovilla, L., Zitvogel, L. & Kroemer, G. The secret ally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discov. 11, 215–233 (2012).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Reginato, E. et al. Photodynamic therapy downregulates the function of regulatory T cells in patients with esophageal squamous cell carcinoma. Photochem. Photobiol. Sci. 13, 1281–1289 (2014).
Sato, K. et al. Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy. Sci. Transl Med. 8, 352ra110 (2016).
Mailer, R. K. et al. IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3. Sci. Rep. 5, 14674 (2015).
Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).
Ware, R. et al. Human CD8+ T lymphocyte clones specific for T cell receptor V beta families expressed |on autologous CD4+ T cells. Immunity 2, 177–184 (1995).
Kiniwa, Y. et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin. Cancer Res. 13, 6947–6958 (2007).
Terabe, M. & Berzofsky, J. A. Tissue-specific roles of NKT cells in tumor immunity. Front. Immunol. 9, 1838 (2018).
Monteiro, M. et al. Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-beta. J. Immunol. 185, 2157–2163 (2010).
Devaud, C. et al. Foxp3 expression in macrophages associated with RENCA tumors in mice. PLOS ONE 9, e108670 (2014).
Mayer, C. T., Kühl, A. A., Loddenkemper, C. & Sparwasser, T. Lack of Foxp3+ macrophages in both untreated and B16 melanoma-bearing mice. Blood 119, 1314–1315 (2012).
Put, S. et al. Macrophages have no lineage history of Foxp3 expression. Blood 119, 1316–1318 (2012).
Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).
Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 71, 3505–3515 (2011).
Noh, J., Noh, G., Kim, H. S., Kim, A. R. & Choi, W. S. Allergen-specific responses of CD19+CD5+Foxp3+ regulatory B cells (Bregs) and CD4+Foxp3+ regulatory T cell (Tregs) in immune tolerance of cow milk allergy of late eczematous reactions. Cell. Immunol. 274, 109–114 (2012).
Zuo, T. et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129, 1275–1286 (2007).
Wang, L. et al. Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16, 336–346 (2009).