Acknowledgement
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government, Ministry of Science and ICT (MSIT) (NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the NRF funded by the MSIT (NRF-2016K1A1A2912755).
References
- Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531-564. https://doi.org/10.1146/annurev.immunol.25.022106.141623
- Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336. https://doi.org/10.1038/ni904
- Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061. https://doi.org/10.1126/science.1079490
- Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20-21. https://doi.org/10.1038/83713
- Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity 2013;39:61-73. https://doi.org/10.1016/j.immuni.2013.07.005
- Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245-1253. https://doi.org/10.4049/jimmunol.167.3.1245
- Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med 2013;5:200ra116.
- Williams JB, Horton BL, Zheng Y, Duan Y, Powell JD, Gajewski TF. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J Exp Med 2017;214:381-400. https://doi.org/10.1084/jem.20160485
- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-264. https://doi.org/10.1038/nrc3239
- Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 2016;8:328rv4.
- Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-2465. https://doi.org/10.1056/NEJMoa1200694
- Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723. https://doi.org/10.1056/NEJMoa1003466
- Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454. https://doi.org/10.1056/NEJMoa1200690
- Togashi Y, Nishikawa H. Regulatory T cells: molecular and cellular basis for immunoregulation. Curr Top Microbiol Immunol 2017;410:3-27. https://doi.org/10.1007/82_2017_58
- Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010;10:490-500. https://doi.org/10.1038/nri2785
- Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7:401-410. https://doi.org/10.1038/ni1318
- Wong J, Obst R, Correia-Neves M, Losyev G, Mathis D, Benoist C. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J Immunol 2007;178:7032-7041. https://doi.org/10.4049/jimmunol.178.11.7032
- Yadav M, Stephan S, Bluestone JA. Peripherally induced Tregs - role in immune homeostasis and autoimmunity. Front Immunol 2013;4:232.
- Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol 2006;24:209-226. https://doi.org/10.1146/annurev.immunol.24.021605.090547
- Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M, Sciume G, Zare H, Vahedi G, Dema B, et al. BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis. Nature 2013;498:506-510. https://doi.org/10.1038/nature12199
- Igarashi K, Kurosaki T, Roychoudhuri R. BACH transcription factors in innate and adaptive immunity. Nat Rev Immunol 2017;17:437-450. https://doi.org/10.1038/nri.2017.26
- Kim EH, Gasper DJ, Lee SH, Plisch EH, Svaren J, Suresh M. Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice. J Immunol 2014;192:985-995. https://doi.org/10.4049/jimmunol.1302378
- Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, et al. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 2017;169:1130-1141.e11. https://doi.org/10.1016/j.cell.2017.05.005
- Sarris M, Andersen KG, Randow F, Mayr L, Betz AG. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 2008;28:402-413. https://doi.org/10.1016/j.immuni.2008.01.012
- Getnet D, Grosso JF, Goldberg MV, Harris TJ, Yen HR, Bruno TC, Durham NM, Hipkiss EL, Pyle KJ, Wada S. A role for the transcription factor Helios in human CD4+CD25+ regulatory T cells. Mol Immunol 2010;47:1595-1600. https://doi.org/10.1016/j.molimm.2010.02.001
- Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010;463:808-812. https://doi.org/10.1038/nature08750
- Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh CS. Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med 2008;205:3105-3117. https://doi.org/10.1084/jem.20081359
- Tran DQ, Ramsey H, Shevach EM. 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 2007;110:2983-2990. https://doi.org/10.1182/blood-2007-06-094656
- Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701-1711. https://doi.org/10.1084/jem.20060772
- Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203:1693-1700. https://doi.org/10.1084/jem.20060468
- Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911. https://doi.org/10.1016/j.immuni.2009.03.019
- Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287-296. https://doi.org/10.1084/jem.188.2.287
- Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S. 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 1998;10:1969-1980. https://doi.org/10.1093/intimm/10.12.1969
- Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997;159:4772-4780. https://doi.org/10.4049/jimmunol.159.10.4772
- Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450:566-569. https://doi.org/10.1038/nature06306
- Turnis ME, Sawant DV, Szymczak-Workman AL, Andrews LP, Delgoffe GM, Yano H, Beres AJ, Vogel P, Workman CJ, Vignali DA. Interleukin-35 limits anti-tumor immunity. Immunity 2016;44:316-329. https://doi.org/10.1016/j.immuni.2016.01.013
- Jarnicki AG, Lysaght J, Todryk S, Mills KH. 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 2006;177:896-904. https://doi.org/10.4049/jimmunol.177.2.896
- Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204:1257-1265. https://doi.org/10.1084/jem.20062512
- Wilson JM, Ross WG, Agbai ON, Frazier R, Figler RA, Rieger J, Linden J, Ernst PB. The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J Immunol 2009;182:4616-4623. https://doi.org/10.4049/jimmunol.0801279
- Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003;9:1269-1274. https://doi.org/10.1038/nm934
- Saleh R, Elkord E. Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett 2019;457:168-179. https://doi.org/10.1016/j.canlet.2019.05.003
- Burchell JT, Strickland DH, Stumbles PA. The role of dendritic cells and regulatory T cells in the regulation of allergic asthma. Pharmacol Ther 2010;125:1-10. https://doi.org/10.1016/j.pharmthera.2009.06.015
- Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271-275. https://doi.org/10.1126/science.1160062
- Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schaffer AA, Gruning BA, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 2014;20:1410-1416. https://doi.org/10.1038/nm.3746
- Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014;345:1623-1627. https://doi.org/10.1126/science.1255904
- Perez VL, Van Parijs L, Biuckians A, Zheng XX, Strom TB, Abbas AK. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 1997;6:411-417. https://doi.org/10.1016/S1074-7613(00)80284-8
- Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999;59:3128-3133.
- 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 1999;163:5211-5218. https://doi.org/10.4049/jimmunol.163.10.5211
- Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K. Targeting VEGFR2 with Ramucirumab strongly impacts effector/activated regulatory T cells and CD8+ T cells in the tumor microenvironment. J Immunother Cancer 2018;6:106.
- Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, et al. Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 2016;22:679-684. https://doi.org/10.1038/nm.4086
- Akimova T, Zhang T, Negorev D, Singhal S, Stadanlick J, Rao A, Annunziata M, Levine MH, Beier UH, Diamond JM, et al. Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors. JCI Insight 2017;2:94075.
- Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-949. https://doi.org/10.1038/nm1093
- Takeuchi Y, Nishikawa H. Roles of regulatory T cells in cancer immunity. Int Immunol 2016;28:401-409. https://doi.org/10.1093/intimm/dxw025
- Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C, Doffin AC, Durand I, Olive D, 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. Cancer Res 2009;69:2000-2009. https://doi.org/10.1158/0008-5472.CAN-08-2360
- Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, Eberlein TJ, Hsieh CS, Linehan DC. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 2009;182:1746-1755. https://doi.org/10.4049/jimmunol.182.3.1746
- Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 2007;67:8900-8905. https://doi.org/10.1158/0008-5472.CAN-07-1866
- Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 2011;60:909-918. https://doi.org/10.1007/s00262-011-1046-y
- Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186-192. https://doi.org/10.1200/JCO.2008.18.7229
- Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NH, Mosseri V, Laccourreye O, Bruneval P, Fridman WH, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006;12:465-472. https://doi.org/10.1158/1078-0432.CCR-05-1886
- Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DH Jr, Patz EF Jr. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 2006;107:2866-2872. https://doi.org/10.1002/cncr.22282
- Marshall EA, Ng KW, Kung SH, Conway EM, Martinez VD, Halvorsen EC, Rowbotham DA, Vucic EA, Plumb AW, Becker-Santos DD, et al. Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis. Mol Cancer 2016;15:67.
- Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298-306. https://doi.org/10.1038/nrc3245
- Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, Ezoe S, Kanakura Y, Sato E, Fukumori Y, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A 2013;110:17945-17950. https://doi.org/10.1073/pnas.1316796110
- De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJ, Provasi E, Sarnicola ML, Panzeri I, et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 2016;45:1135-1147. https://doi.org/10.1016/j.immuni.2016.10.021
- Nishikawa H, Kato T, Tawara I, Saito K, Ikeda H, Kuribayashi K, Allen PM, Schreiber RD, Sakaguchi S, Old LJ, et al. Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells. J Exp Med 2005;201:681-686. https://doi.org/10.1084/jem.20041959
- Nishikawa H, Kato T, Tawara I, Ikeda H, Kuribayashi K, Allen PM, Schreiber RD, Old LJ, Shiku H. IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. J Immunol 2005;175:4433-4440. https://doi.org/10.4049/jimmunol.175.7.4433
- Pace L, Tempez A, Arnold-Schrauf C, Lemaitre F, Bousso P, Fetler L, Sparwasser T, Amigorena S. Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 2012;338:532-536. https://doi.org/10.1126/science.1227049
- Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, Saito T, Nishioka M, Wing JB, Adeegbe D, Katayama I, et al. Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals. Science 2014;346:1536-1540. https://doi.org/10.1126/science.aaa1292
- Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 2014;27:1-7. https://doi.org/10.1016/j.coi.2013.12.005
- Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, 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 2015;21:4327-4336. https://doi.org/10.1158/1078-0432.CCR-15-0357
- Jia Z, Zhao R, Tian Y, Huang Z, Tian Z, Shen Z, Wang Q, Wang J, Fu X, Wu Y, et al. A novel splice variant of FR4 predominantly expressed in CD4+CD25+ regulatory T cells. Immunol Invest 2009;38:718-729. https://doi.org/10.3109/08820130903171003
- Miyara M, Chader D, Sage E, Sugiyama D, Nishikawa H, Bouvry D, Claer L, Hingorani R, Balderas R, Rohrer J, et al. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. Proc Natl Acad Sci U S A 2015;112:7225-7230. https://doi.org/10.1073/pnas.1508224112
- Foss F. Clinical experience with denileukin diftitox (ONTAK). Semin Oncol 2006;33:S11-S16. https://doi.org/10.1053/j.seminoncol.2005.12.017
- Steitz J, Bruck J, Lenz J, Knop J, Tuting T. 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. Cancer Res 2001;61:8643-8646.
- Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ Jr, Colligon TA, Trosko JA, Leinbach LI, Pletcher CH, et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 2012;4:134ra62.
- Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM, Scharenborg NM, Klasen IS, Hilbrands LB, Figdor CG, de Vries IJ, 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 2010;16:5067-5078. https://doi.org/10.1158/1078-0432.CCR-10-1757
- Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P, Speiser DE. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A 2015;112:6140-6145. https://doi.org/10.1073/pnas.1417320112
- Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012;366:2517-2519. https://doi.org/10.1056/NEJMe1205943
- Arce Vargas F, Furness AJ, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 2018;33:649-663.e4. https://doi.org/10.1016/j.ccell.2018.02.010
- Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Wilson NS, Dranoff G, Brogdon JL. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med 2013;210:1685-1693. https://doi.org/10.1084/jem.20130573
- Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, Korman AJ. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res 2013;1:32-42. https://doi.org/10.1158/2326-6066.CIR-13-0013
- Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, 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 2013;210:1695-1710. https://doi.org/10.1084/jem.20130579
- van Olffen RW, Koning N, van Gisbergen KP, Wensveen FM, Hoek RM, Boon L, Hamann J, van Lier RA, Nolte MA. GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo. J Immunol 2009;182:7490-7500. https://doi.org/10.4049/jimmunol.0802751
- Nishikawa H, Kato T, Hirayama M, Orito Y, Sato E, Harada N, Gnjatic S, Old LJ, Shiku H. Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling. Cancer Res 2008;68:5948-5954. https://doi.org/10.1158/0008-5472.CAN-07-5839
- Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood 2018;131:39-48. https://doi.org/10.1182/blood-2017-07-741025
- Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, Walker J, Gonzalez I, Meeuwsen T, Fox BA, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 2013;73:7189-7198. https://doi.org/10.1158/0008-5472.CAN-12-4174
- Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 2004;199:1479-1489. https://doi.org/10.1084/jem.20040179
- Burmeister Y, Lischke T, Dahler AC, Mages HW, Lam KP, Coyle AJ, Kroczek RA, Hutloff A. ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol 2008;180:774-782. https://doi.org/10.4049/jimmunol.180.2.774
- Nagase H, Takeoka T, Urakawa S, Morimoto-Okazawa A, Kawashima A, Iwahori K, Takiguchi S, Nishikawa H, Sato E, Sakaguchi S, et al. ICOS+ Foxp3+ TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori. Int J Cancer 2017;140:686-695. https://doi.org/10.1002/ijc.30475
- Burris HA, Callahan MK, Tolcher AW, Kummar S, Falchook GS, Pachynski RK, Tykodi SS, Gibney GT, Seiwert TY, Gainor JF, 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. J Clin Oncol 2017;35:3033.
- Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, Smyth MJ, Kuchroo VK, Anderson AC. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 2015;125:4053-4062. https://doi.org/10.1172/JCI81187
- Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 2014;40:569-581. https://doi.org/10.1016/j.immuni.2014.02.012
- Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, Park S, Javinal V, Chiu H, Irving B, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 2014;26:923-937. https://doi.org/10.1016/j.ccell.2014.10.018
- Scurr M, Ladell K, Besneux M, Christian A, Hockey T, Smart K, Bridgeman H, Hargest R, Phillips S, Davies M, et al. Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3- T cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T cells. Mucosal Immunol 2014;7:428-439. https://doi.org/10.1038/mi.2013.62
- Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016;44:989-1004. https://doi.org/10.1016/j.immuni.2016.05.001
- Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005;6:1245-1252. https://doi.org/10.1038/ni1271
- Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 2017;276:97-111. https://doi.org/10.1111/imr.12520
- Sakuishi K, Ngiow SF, Sullivan JM, Teng MW, Kuchroo VK, Smyth MJ, Anderson AC. TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. OncoImmunology 2013;2:e23849.
- Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 2011;11:119-130. https://doi.org/10.1038/nri2916
- Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 2006;97:1139-1146. https://doi.org/10.1111/j.1349-7006.2006.00307.x
- Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 2010;127:759-767. https://doi.org/10.1002/ijc.25429
- Kurose K, Ohue Y, Oka M. Anti-CCR4 mAb and regulatory T cells. Gan To Kagaku Ryoho 2013;40:1150-1155.
- 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 U S A 2016;113:8490-8495. https://doi.org/10.1073/pnas.1608873113
- Gianchecchi E, Fierabracci A. Inhibitory receptors and pathways of lymphocytes: the role of PD-1 in Treg development and their involvement in autoimmunity onset and cancer progression. Front Immunol 2018;9:2374.
- Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A 2019;116:9999-10008. https://doi.org/10.1073/pnas.1822001116
- Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer 2017;3:56-71. https://doi.org/10.1016/j.trecan.2016.11.008
- Holmgaard RB, Schaer DA, Li Y, Castaneda SP, Murphy MY, Xu X, Inigo I, Dobkin J, Manro JR, Iversen PW, 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 2018;6:47.
- Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, Marte JL, Donahue RN, Grenga I, et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin Cancer Res 2018;24:1287-1295. https://doi.org/10.1158/1078-0432.CCR-17-2653
- Ahmad S, Abu-Eid R, Shrimali R, Webb M, Verma V, Doroodchi A, Berrong Z, Samara R, Rodriguez PC, Mkrtichyan M, et al. Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of T regulatory cells to enhance cancer immunotherapy. Cancer Res 2017;77:1892-1904. https://doi.org/10.1158/0008-5472.CAN-16-1839
- Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 2014;510:407-411. https://doi.org/10.1038/nature13444
- Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 2015;16:188-196. https://doi.org/10.1038/ni.3077
- Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 2015;16:178-187. https://doi.org/10.1038/ni.3076
- Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, Ishida Y, Kumagai T, Sato S, Ohashi K, 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 2015;2:e528-e535. https://doi.org/10.1016/S2352-3026(15)00196-9
- Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 2014;41:722-736. https://doi.org/10.1016/j.immuni.2014.10.012
- Ohta A, Sitkovsky M. Extracellular adenosine-mediated modulation of regulatory T cells. Front Immunol 2014;5:304.
- Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 2013;73:539-549. https://doi.org/10.1158/0008-5472.CAN-12-2325
- Zhu P, Hu C, Hui K, Jiang X. The role and significance of VEGFR2+ regulatory T cells in tumor immunity. Onco Targets Ther 2017;10:4315-4319. https://doi.org/10.2147/OTT.S142085
- Roland CL, Lynn KD, Toombs JE, Dineen SP, Udugamasooriya DG, Brekken RA. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One 2009;4:e7669.
- Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2015;212:139-148. https://doi.org/10.1084/jem.20140559