CTLA-4 in Regulatory T Cells for Cancer Immunotherapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Mechanism of CTLA-4 Immune System Inhibition
3. Regulatory T Cells and Anticancer Immunity
3.1. First Insights into Treg Cells
3.2. Inhibitory Effects of Treg Cells on APC
3.3. Conflicting Roles of Treg Cells in Malignant Tumors
3.4. Treg Cells and the Tumor Microenvironment
3.5. Cross-Talk between Treg Cells and the Tumor Microenvironment
3.6. Treg Cells and Nonself Antigens
4. Correlation between Anti-CTLA-4 Treatment and Its Effect on Treg Cells
5. Conclusive Remarks and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
- Miller, K.D.D.; Fidler-Benaoudia, M.; Keegan, T.H.H.; Hipp, H.S.S.; Jemal, A.; Siegel, R.L.L. Cancer statistics for adolescents and young adults, 2020. CA Cancer J. Clin. 2020, 70, 443–459. [Google Scholar] [CrossRef]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [Green Version]
- Speiser, D.E.E.; Ho, P.C.C.; Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 2016, 16, 599–611. [Google Scholar]
- Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 2006, 6, 295–307. [Google Scholar]
- Kennedy, R.; Celis, E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol. Rev. 2008, 222, 129–144. [Google Scholar]
- Melssen, M.; Slingluff, C.L. Vaccines targeting helper T cells for cancer immunotherapy. Curr. Opin. Immunol. 2017, 47, 85–92. [Google Scholar]
- Borst, J.; Ahrends, T.; Bąbała, N.; Melief, C.J.M.; Kastenmüller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 2018, 18, 635–647. [Google Scholar]
- Raskov, H.; Orhan, A.; Christensen, J.P.; Gögenur, I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br. J. Cancer 2021, 124, 359–367. [Google Scholar]
- Raverdeau, M.; Cunningham, S.P.; Harmon, C.; Lynch, L. γδ T cells in cancer: A small population of lymphocytes with big implications. Clin. Transl. Immunol. 2019, 8. [Google Scholar] [CrossRef]
- Bennstein, S.B. Unraveling natural killer T-cells development. Front. Immunol. 2018, 8, 1950. [Google Scholar]
- Toubal, A.; Nel, I.; Lotersztajn, S.; Lehuen, A. Mucosal-associated invariant T cells and disease. Nat. Rev. Immunol. 2019, 19, 643–657. [Google Scholar]
- Bedoui, S.; Gebhardt, T.; Gasteiger, G.; Kastenmüller, W. Parallels and differences between innate and adaptive lymphocytes. Nat. Immunol. 2016, 17, 490–494. [Google Scholar]
- Kronenberg, M. Toward an understanding of NKT cell biology: Progress and paradoxes. Annu. Rev. Immunol. 2005, 23, 877–900. [Google Scholar]
- Van Kaer, L.; Postoak, J.L.; Wang, C.; Yang, G.; Wu, L. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell. Mol. Immunol. 2019, 16, 531–539. [Google Scholar]
- Vantourout, P.; Hayday, A. Six-of-the-best: Unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 2013, 13, 88–100. [Google Scholar]
- Chien, Y.H.; Meyer, C.; Bonneville, M. γδ T cells: First line of defense and beyond. Annu. Rev. Immunol. 2014, 32, 121–155. [Google Scholar]
- Lantz, O.; Legoux, F. MAIT cells: An historical and evolutionary perspective. Immunol. Cell Biol. 2018, 96, 564–572. [Google Scholar] [CrossRef]
- Keller, A.N.; Corbett, A.J.; Wubben, J.M.; McCluskey, J.; Rossjohn, J. MAIT cells and MR1-antigen recognition. Curr. Opin. Immunol. 2017, 46, 66–74. [Google Scholar]
- Mougiakakos, D.; Johansson, C.C.C.; Trocme, E.; All-Ericsson, C.; Economou, M.A.A.; Larsson, O.; Seregard, S.; Kiessling, R. Intratumoral forkhead box p3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma. Cancer 2010, 116, 2224–2233. [Google Scholar] [CrossRef]
- Piccirillo, C.A.A. Regulatory T cells in health and disease. Cytokine 2008, 43, 395–401. [Google Scholar]
- Maj, T.; Wang, W.; Crespo, J.; Zhang, H.; Wang, W.; Wei, S.; Zhao, L.; Vatan, L.; Shao, I.; Szeliga, W.; et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 2017, 18, 1332–1341. [Google Scholar] [CrossRef]
- Vanamee, É.S.S.; Faustman, D.L.L. TNFR2: A Novel Target for Cancer Immunotherapy. Trends Mol. Med. 2017, 23, 1037–1046. [Google Scholar]
- Zeng, G.; Jin, L.; Ying, Q.; Chen, H.; Thembinkosi, M.C.C.; Yang, C.; Zhao, J.; Ji, H.; Lin, S.; Peng, R.; et al. Regulatory T cells in cancer immunotherapy: Basic research outcomes and clinical directions. Cancer Manag. Res. 2020, 12, 10411–10421. [Google Scholar]
- Togashi, Y.; Shitara, K.; Nishikawa, H. Regulatory T cells in cancer immunosuppression—Implications for anticancer therapy. Nat. Rev. Clin. Oncol. 2019, 16, 356–371. [Google Scholar]
- Atkins, M.B.B.; Clark, J.I.I.; Quinn, D.I.I. Immune checkpoint inhibitors in advanced renal cell carcinoma: Experience to date and future directions. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2017, 28, 1484–1494. [Google Scholar]
- Foell, J.; Hewes, B. T Cell Costimulatory and Inhibitory Receptors as Therapeutic Targets for Inducing Anti-Tumor Immunity. Curr. Cancer Drug Targets 2007, 7, 55–70. [Google Scholar] [CrossRef]
- Wei, S.C.; Duffy, C.R.; Allison, J.P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018, 8, 1069–1086. [Google Scholar] [CrossRef] [Green Version]
- Pentcheva-Hoang, T.; Egen, J.G.; Wojnoonski, K.; Allison, J.P. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 2004, 21, 401–413. [Google Scholar] [CrossRef] [Green Version]
- Walunas, T.L.; Lenschow, D.J.; Bakker, C.Y.; Linsley, P.S.; Freeman, G.J.; Green, J.M.; Thompson, C.B.; Bluestone, J.A. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994, 1, 405–413. [Google Scholar] [CrossRef]
- Brunner, M.C.; Chambers, C.A.; Chan, F.K.; Hanke, J.; Winoto, A.; Allison, J.P. CTLA-4-Mediated inhibition of early events of T cell proliferation—PubMed. Available online: https://pubmed.ncbi.nlm.nih.gov/10229815/ (accessed on 18 November 2020).
- Linsley, P.S.; Brady, W.; Urnes, M.; Grosmaire, L.S.; Damle, N.K.; Ledbetter, J.A. CTLA4 is a second receptor for the b cell activation antigen B7. J. Exp. Med. 1991, 174, 561–569. [Google Scholar] [CrossRef] [Green Version]
- Linsley, P.S.; Greene, J.A.L.; Brady, W.; Bajorath, J.; Ledbetter, J.A.; Peach, R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994, 1, 793–801. [Google Scholar] [CrossRef]
- Lanier, L.L.; O’Fallon, S.; Somoza, C.; Phillips, J.H.; Linsley, P.S.; Okumura, K.; Ito, D.; Azuma, M. CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J. Immunol. 1995, 154, 97–105. [Google Scholar]
- Van Der Merwe, P.A.; Bodian, D.L.; Daenke, S.; Linsley, P.; Davis, S.J. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J. Exp. Med. 1997, 185, 393–403. [Google Scholar] [CrossRef] [Green Version]
- Yi, J.; Kawabe, T.; Sprent, J. New insights on T-cell self-tolerance. Curr. Opin. Immunol. 2020, 63, 14–20. [Google Scholar]
- Qureshi, O.S.; Zheng, Y.; Nakamura, K.; Attridge, K.; Manzotti, C.; Schmidt, E.M.; Baker, J.; Jeffery, L.E.; Kaur, S.; Briggs, Z.; et al. Trans-endocytosis of CD80 and CD86: A molecular basis for the cell-extrinsic function of CTLA-4. Science 2011, 332, 600–603. [Google Scholar] [CrossRef] [Green Version]
- Bachmann, M.F.; Köhler, G.; Ecabert, B.; Mak, T.W.; Kopf, M. Cutting Edge: Lymphoproliferative Disease in the Absence of CTLA-4 is Not T Cell Autonomous—PubMed. Available online: https://pubmed.ncbi.nlm.nih.gov/10415006/ (accessed on 19 November 2020).
- 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. [Google Scholar] [CrossRef]
- Yang, Y.; Li, X.; Ma, Z.; Wang, C.; Yang, Q.; Byrne-Steele, M.; Hong, R.; Min, Q.; Zhou, G.; Cheng, Y.; et al. CTLA-4 expression by B-1a B cells is essential for immune tolerance. Nat. Commun. 2021, 12, 1–17. [Google Scholar] [CrossRef]
- Egen, J.G.; Allison, J.P. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002, 16, 23–35. [Google Scholar] [CrossRef] [Green Version]
- Pagès, F.; Ragueneau, M.; Rottapel, R.; Truneh, A.; Nunes, J.; Imbert, J.; Olive, D. Binding of phosphatidyl-inositol-3-OH kinase to CD28 is required for T-cell signalling. Nature 1994, 369, 327–329. [Google Scholar] [CrossRef]
- Kane, L.P.; Andres, P.G.; Howland, K.C.; Abbas, A.K.; Weiss, A. Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines. Nat. Immunol. 2001, 2, 37–44. [Google Scholar] [CrossRef]
- Chambers, C.A.; Cado, D.; Truong, T.; Allison, J.P. Thymocyte development is normal in CTLA-4-deficient mice. Proc. Natl. Acad. Sci. USA 1997, 94, 9296–9301. [Google Scholar] [CrossRef] [Green Version]
- Waterhouse, P.; Penninger, J.M.; Timms, E.; Wakeham, A.; Shahinian, A.; Lee, K.P.; Thompson, C.B.; Griesser, H.; Mak, T.W. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995, 270, 985–988. [Google Scholar] [CrossRef]
- Tivol, E.A.; Borriello, F.; Schweitzer, A.N.; Lynch, W.P.; Bluestone, J.A.; Sharpe, A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995, 3, 541–547. [Google Scholar] [CrossRef] [Green Version]
- Friedline, R.H.; Brown, D.S.; Nguyen, H.; Kornfeld, H.; Lee, J.; Zhang, Y.; Appleby, M.; Der, S.D.; Kang, J.; Chambers, C.A. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J. Exp. Med. 2009, 206, 421–434. [Google Scholar] [CrossRef] [Green Version]
- Quezada, S.A.; Peggs, K.S.; Curran, M.A.; Allison, J.P. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Investig. 2006, 116, 1935–1945. [Google Scholar] [CrossRef] [Green Version]
- Sharma, A.; Subudhi, S.K.; Blando, J.; Scutti, J.; Vence, L.; Wargo, J.; Allison, J.P.; Ribas, A.; Sharma, P. Anti-CTLA-4 immunotherapy does not deplete Foxp3 þ regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. 2019, 25, 1233–1238. [Google Scholar] [CrossRef] [Green Version]
- Jain, N.; Nguyen, H.; Chambers, C.; Kang, J. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc. Natl. Acad. Sci. USA 2010, 107, 1524–1528. [Google Scholar] [CrossRef] [Green Version]
- Corse, E.; Allison, J.P. Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans. J. Immunol. 2012, 189, 1123–1127. [Google Scholar] [CrossRef] [Green Version]
- Paterson, A.M.; Lovitch, S.B.; Sage, P.T.; Juneja, V.R.; Lee, Y.; Trombley, J.D.; Arancibia-Cárcamo, C.V.; Sobel, R.A.; Rudensky, A.Y.; Kuchroo, V.K.; et al. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J. Exp. Med. 2015, 212, 1603–1621. [Google Scholar] [CrossRef]
- Doyle, A.M.; Mullen, A.C.; Villarino, A.V.; Hutchins, A.S.; High, F.A.; Lee, H.W.; Thompson, C.B.; Reiner, S.L. Induction of cytotoxic T lymphocyte antigen 4 (CTLA-4) restricts clonal expansion of helper T cells. J. Exp. Med. 2001, 194, 893–902. [Google Scholar] [CrossRef] [Green Version]
- Egen, J.G.; Kuhns, M.S.; Allison, J.P. CTLA-4: New insights into its biological function and use in tumor immunotherapy. Nat. Immunol. 2002, 3, 611–618. [Google Scholar]
- Busch, D.H.; Pamer, E.G. T cell affinity maturation by selective expansion during infection. J. Exp. Med. 1999, 189, 701–709. [Google Scholar] [CrossRef]
- Savage, P.A.; Boniface, J.J.; Davis, M.M. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 1999, 10, 485–492. [Google Scholar] [CrossRef] [Green Version]
- Metzler, W.J.; Bajorath, J.; Fenderson, W.; Shaw, S.Y.; Constantine, K.L.; Naemura, J.; Leytze, G.; Peach, R.J.; Lavoie, T.B.; Mueller, L.; et al. Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Nat. Struct. Biol. 1997, 4, 527–531. [Google Scholar] [CrossRef]
- Yu, C.; Sonnen, A.F.P.; George, R.; Dessailly, B.H.; Stagg, L.J.; Evans, E.J.; Orengo, C.A.; Stuart, D.I.; Ladbury, J.E.; Ikemizu, S.; et al. Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering. J. Biol. Chem. 2011, 286, 6685–6696. [Google Scholar] [CrossRef] [Green Version]
- Stamper, C.C.; Zhang, Y.; Tobin, J.F.; Erbe, D.V.; Ikemizu, S.; Davis, S.J.; Stahl, M.L.; Seehra, J.; Somers, W.S.; Mosyak, L. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 2001, 410, 608–611. [Google Scholar] [CrossRef]
- Schwartz, J.C.D.; Zhang, X.; Fedorov, A.A.; Nathenson, S.G.; Almo, S.C. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 2001, 410, 604–608. [Google Scholar] [CrossRef]
- Zhang, F.; Qi, X.; Wang, X.; Wei, D.; Wu, J.; Feng, L.; Cai, H.; Wang, Y.; Zeng, N.; Xu, T.; et al. Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab. Oncotarget 2017, 8, 90215–90224. [Google Scholar] [CrossRef] [Green Version]
- Ramagopal, U.A.; Liu, W.; Garrett-Thomson, S.C.; Bonanno, J.B.; Yan, Q.; Srinivasan, M.; Wong, S.C.; Bell, A.; Mankikar, S.; Rangan, V.S.; et al. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. Proc. Natl. Acad. Sci. USA 2017, 114, E4223–E4232. [Google Scholar] [CrossRef] [Green Version]
- He, M.; Chai, Y.; Qi, J.; Zhang, C.W.H.; Tong, Z.; Shi, Y.; Yan, J.; Tan, S.; Gao, G.F. Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget 2017, 8, 67129–67139. [Google Scholar] [CrossRef] [Green Version]
- Hueber, A.J.; Matzkies, F.G.; Rahmeh, M.; Manger, B.; Kalden, J.R.; Nagel, T. CTLA-4 lacking the cytoplasmic domain costimulates IL-2 production in T-cell hybridomas. Immunol. Cell Biol. 2006, 84, 51–58. [Google Scholar] [CrossRef]
- Rudd, C.E. The reverse stop-signal model for CTLA4 function. Nat. Rev. Immunol. 2008, 8, 153–160. [Google Scholar]
- Thompson, C.B.; Allison, J.P. The emerging role of CTLA-4 as an immune attenuator. Immunity 1997, 7, 445–450. [Google Scholar]
- Waterhouse, P.; Marengère, L.E.M.; Mittrücker, H.W.; Mak, T.W. CTLA-4, a negative regulator of T-Lymphocyte activation. Immunol. Rev. 1996, 153, 183–207. [Google Scholar]
- Marengère, L.E.M.; Waterhouse, P.; Duncan, G.S.; Mittrücker, H.W.; Feng, G.S.; Mak, T.W. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 1996, 272, 1170–1173. [Google Scholar] [CrossRef]
- Wang, H.; Sun, Y.; Zhou, X.; Chen, C.; Jiao, L.; Li, W.; Gou, S.; Li, Y.; Du, J.; Chen, G.; et al. CD47/SIRPα blocking peptide identification and synergistic effect with irradiation for cancer immunotherapy. J. Immunother. Cancer 2020, 8, 905. [Google Scholar] [CrossRef]
- Kaspar, A.A.; Reichert, J.M. Future directions for peptide therapeutics development. Drug Discov. Today 2013, 18, 807–817. [Google Scholar]
- Xie, J.; Si, X.; Gu, S.; Wang, M.; Shen, J.; Li, H.; Li, D.; Fang, Y.; Liu, C.; Zhu, J. Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment. J. Med. Chem. 2017, 60, 10205–10219. [Google Scholar] [CrossRef]
- Song, K.; Liu, X.; Huang, W.; Lu, S.; Shen, Q.; Zhang, L.; Zhang, J. Improved Method for the Identification and Validation of Allosteric Sites. J. Chem. Inf. Model. 2017, 57, 2358–2363. [Google Scholar] [CrossRef]
- Roca, C.; Requena, C.; Sebastián-Pérez, V.; Malhotra, S.; Radoux, C.; Pérez, C.; Martinez, A.; Antonio Páez, J.; Blundell, T.L.; Campillo, N.E. Identification of new allosteric sites and modulators of AChE through computational and experimental tools. J. Enzyme Inhib. Med. Chem. 2018, 33, 1034–1047. [Google Scholar] [CrossRef] [Green Version]
- 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. 1995, 155, 1151–1164. [Google Scholar]
- Bennett, C.L.; Christie, J.; Ramsdell, F.; Brunkow, M.E.; Ferguson, P.J.; Whitesell, L.; Kelly, T.E.; Saulsbury, F.T.; Chance, P.F.; Ochs, H.D. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 2001, 27, 20–21. [Google Scholar] [CrossRef]
- Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. J. Immunol. 2017, 198, 986–992. [Google Scholar] [CrossRef]
- Brunkow, M.E.; Jeffery, E.W.; Hjerrild, K.A.; Paeper, B.; Clark, L.B.; Yasayko, S.A.; Wilkinson, J.E.; Galas, D.; Ziegler, S.F.; Ramsdell, F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 2001, 27, 68–73. [Google Scholar] [CrossRef]
- Linterman, M.A.; Pierson, W.; Lee, S.K.; Kallies, A.; Kawamoto, S.; Rayner, T.F.; Srivastava, M.; Divekar, D.P.; Beaton, L.; Hogan, J.J.; et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 2011, 17, 975–982. [Google Scholar] [CrossRef] [Green Version]
- Koch, M.A.; Tucker-Heard, G.; Perdue, N.R.; Killebrew, J.R.; Urdahl, K.B.; Campbell, D.J. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 2009, 10, 595–602. [Google Scholar] [CrossRef]
- Chung, Y.; Tanaka, S.; Chu, F.; Nurieva, R.I.; Martinez, G.J.; Rawal, S.; Wang, Y.H.; Lim, H.; Reynolds, J.M.; Zhou, X.H.; et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 2011, 17, 983–988. [Google Scholar] [CrossRef]
- Chaudhry, A.; Rudra, D.; Treuting, P.; Samstein, R.M.; Liang, Y.; Kas, A.; Rudensky, A.Y. CD4+ regulatory T cells control TH17 responses in a stat3-dependent manner. Science 2009, 326, 986–991. [Google Scholar] [CrossRef] [Green Version]
- Wing, K.; Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 2010, 11, 7–13. [Google Scholar]
- Sakaguchi, S.; Miyara, M.; Costantino, C.M.; Hafler, D.A. FOXP3 + regulatory T cells in the human immune system. Nat. Rev. Immunol. 2010, 10, 490–500. [Google Scholar]
- Togashi, Y.; Nishikawa, H. Regulatory T cells: Molecular and cellular basis for immunoregulation. In Current Topics in Microbiology and Immunology; Springer: Berlin, Germany, 2017; Volume 410, pp. 3–27. [Google Scholar]
- Hori, S.; Nomura, T.; Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. J. Immunol. 2017, 198, 981–985. [Google Scholar] [CrossRef] [Green Version]
- Khattri, R.; Cox, T.; Yasayko, S.A.; Ramsdell, F. An essential role for Scurfin in CD4+CD25+T regulatory cells. J. Immunol. 2017, 198, 993–998. [Google Scholar] [CrossRef]
- Steinbrink, K.; Wölfl, M.; Jonuleit, H.; Knop, J.; Enk, A.H.H. Induction of tolerance by IL-10-treated dendritic cells. J. Immunol. 1997, 159, 4772–4780. [Google Scholar]
- Collison, L.W.W.; Workman, C.J.J.; Kuo, T.T.T.; Boyd, K.; Wang, Y.; Vignali, K.M.M.; Cross, R.; Sehy, D.; Blumberg, R.S.S.; Vignali, D.A.A.A.A. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007, 450, 566–569. [Google Scholar] [CrossRef]
- Turnis, M.E.E.; Sawant, D.V.V.; Szymczak-Workman, A.L.L.; Andrews, L.P.P.; Delgoffe, G.M.M.; Yano, H.; Beres, A.J.J.; Vogel, P.; Workman, C.J.J.; Vignali, D.A. Interleukin-35 Limits Anti-Tumor Immunity. Immunity 2016, 44, 316–329. [Google Scholar] [CrossRef] [Green Version]
- Jarnicki, A.G.G.; Lysaght, J.; Todryk, S.; Mills, K.H.G.H.G. Suppression of Antitumor Immunity by IL-10 and TGF-β-Producing T Cells Infiltrating the Growing Tumor: Influence of Tumor Environment on the Induction of CD4+ and CD8+ Regulatory T Cells. J. Immunol. 2006, 177, 896–904. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Thornton, A.M.M.; Shevach, E.M.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 1998, 188, 287–296. [Google Scholar] [CrossRef] [Green Version]
- Perez, V.L.L.; Van Parijs, L.; Biuckians, A.; Zheng, X.X.X.; Strom, T.B.B.; Abbas, A.K.K. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 1997, 6, 411–417. [Google Scholar] [CrossRef] [Green Version]
- Onizuka, S.; Tawara, I.; Shimizu, J.; Sakaguchi, S.; Fujita, T.; Nakayama, E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res. 1999, 59, 3128–3133. [Google Scholar]
- Shimizu, J.; Yamazaki, S.; Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: A common basis between tumor immunity and autoimmunity—PubMed. J. Immunol. 1999, 163, 5211–5218. [Google Scholar]
- Lodish, H.; Berk, A.; Zipursky, S.L.; Matsudaira, P.; Baltimore, D.; Darnell, J. Proto-Oncogenes and Tumor-Suppressor Genes. In Molecular Cell Biology, 4th ed.; W. H. Freeman: New York, NY, USA, 2000. [Google Scholar]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Fridman, W.H.; Pagès, F.; Sautès-Fridman, C.; Galon, J. The immune contexture in human tumours: Impact on clinical outcome. Nat. Rev. Cancer 2012, 12, 298–306. [Google Scholar]
- Shang, B.; Liu, Y.; Jiang, S.J.; Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Sci. Rep. 2015, 5. [Google Scholar] [CrossRef] [Green Version]
- Kryczek, I.; Wu, K.; Zhao, E.; Wei, S.; Vatan, L.; Szeliga, W.; Huang, E.; Greenson, J.; Chang, A.; Roliński, J.; et al. IL-17 + Regulatory T Cells in the Microenvironments of Chronic Inflammation and Cancer. J. Immunol. 2011, 186, 4388–4395. [Google Scholar] [CrossRef] [Green Version]
- Kryczek, I.; Liu, R.; Wang, G.; Wu, K.; Shu, X.; Szeliga, W.; Vatan, L.; Finlayson, E.; Huang, E.; Simeone, D.; et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res. 2009, 69, 3995–4000. [Google Scholar] [CrossRef] [Green Version]
- Colbeck, E.J.; Jones, E.; Hindley, J.P.; Smart, K.; Schulz, R.; Browne, M.; Cutting, S.; Williams, A.; Parry, L.; Godkin, A.; et al. Treg depletion licenses T cell–driven HEV neogenesis and promotes tumor destruction. Cancer Immunol. Res. 2017, 5, 1005–1015. [Google Scholar] [CrossRef] [Green Version]
- Hindley, J.P.; Jones, E.; Smart, K.; Bridgeman, H.; Lauder, S.N.; Ondondo, B.; Cutting, S.; Ladell, K.; Wynn, K.K.; Withers, D.; et al. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Cancer Res. 2012, 72, 5473–5482. [Google Scholar] [CrossRef] [Green Version]
- 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. USA 2013, 110, 17945–17950. [Google Scholar] [CrossRef] [Green Version]
- Facciabene, A.; Peng, X.; Hagemann, I.S.; Balint, K.; Barchetti, A.; Wang, L.P.; Gimotty, P.A.; Gilks, C.B.; Lal, P.; Zhang, L.; et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T reg cells. Nature 2011, 475, 226–230. [Google Scholar] [CrossRef]
- Togashi, Y.; Nishikawa, H. Suppression from beyond the grave. Nat. Immunol. 2017, 18, 1285–1286. [Google Scholar]
- Nishikawa, H.; Kato, T.; Tawara, I.; Saito, K.; Ikeda, H.; Kuribayashi, K.; Allen, P.M.; Schreiber, R.D.; Sakaguchi, S.; Old, L.J.; et al. Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells. J. Exp. Med. 2005, 201, 681–686. [Google Scholar] [CrossRef]
- Ghiringhelli, F.; Puig, P.E.; Roux, S.; Parcellier, A.; Schmitt, E.; Solary, E.; Kroemer, G.; Martin, F.; Chauffert, B.; Zitvogel, L. Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4 +CD25 + regulatory T cell proliferation. J. Exp. Med. 2005, 202, 919–929. [Google Scholar] [CrossRef] [Green Version]
- Hindley, J.P.; Ferreira, C.; Jones, E.; Lauder, S.N.; Ladell, K.; Wynn, K.K.; Betts, G.J.; Singh, Y.; Price, D.A.; Godkin, A.J.; 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. 2011, 71, 736–746. [Google Scholar] [CrossRef] [Green Version]
- 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. 2012, 72, 3557–3569. [Google Scholar] [CrossRef] [Green Version]
- Morikawa, H.; Ohkura, N.; Vandenbon, A.; Itoh, M.; Nagao-Sato, S.; Kawaji, H.; Lassmann, T.; Carninci, P.; Hayashizaki, Y.; Forrest, A.R.R.; et al. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl. Acad. Sci. USA 2014, 111, 5289–5294. [Google Scholar] [CrossRef] [Green Version]
- Wei, G.; Wei, L.; Zhu, J.; Zang, C.; Hu-Li, J.; Yao, Z.; Cui, K.; Kanno, Y.; Roh, T.Y.; Watford, W.T.; et al. Global Mapping of H3K4me3 and H3K27me3 Reveals Specificity and Plasticity in Lineage Fate Determination of Differentiating CD4+ T Cells. Immunity 2009, 30, 155–167. [Google Scholar] [CrossRef] [Green Version]
- Ohkura, N.; Hamaguchi, M.; Morikawa, H.; Sugimura, K.; Tanaka, A.; Ito, Y.; Osaki, M.; Tanaka, Y.; Yamashita, R.; Nakano, N.; et al. T Cell Receptor Stimulation-Induced Epigenetic Changes and Foxp3 Expression Are Independent and Complementary Events Required for Treg Cell Development. Immunity 2012, 37, 785–799. [Google Scholar] [CrossRef] [Green Version]
- Curiel, T.J.; Coukos, G.; Zou, L.; Alvarez, X.; Cheng, P.; Mottram, P.; Evdemon-Hogan, M.; Conejo-Garcia, J.R.; 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. [Google Scholar] [CrossRef]
- Wei, S.; Kryczek, I.; Edwards, R.P.; Zou, L.; Szeliga, W.; Banerjee, M.; Cost, M.; Cheng, P.; Chang, A.; Redman, B.; et al. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res. 2007, 67, 7487–7494. [Google Scholar] [CrossRef] [Green Version]
- Tan, M.C.B.; Goedegebuure, P.S.; Belt, B.A.; Flaherty, B.; Sankpal, N.; Gillanders, W.E.; Eberlein, T.J.; Hsieh, C.-S.; Linehan, D.C. 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. [Google Scholar] [CrossRef]
- Hoelzinger, D.B.; Smith, S.E.; Mirza, N.; Dominguez, A.L.; Manrique, S.Z.; Lustgarten, J. Blockade of CCL1 Inhibits T Regulatory Cell Suppressive Function Enhancing Tumor Immunity without Affecting T Effector Responses. J. Immunol. 2010, 184, 6833–6842. [Google Scholar] [CrossRef] [Green Version]
- Sen, D.R.; Kaminski, J.; Barnitz, R.A.; Kurachi, M.; Gerdemann, U.; Yates, K.B.; Tsao, H.W.; Godec, J.; LaFleur, M.W.; Brown, F.D.; et al. The epigenetic landscape of T cell exhaustion. Science 2016, 354, 1165–1169. [Google Scholar] [CrossRef] [Green Version]
- Spranger, S.; Spaapen, R.M.; Zha, Y.; Williams, J.; Meng, Y.; Ha, T.T.; Gajewski, T.F. 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. [Google Scholar]
- Williams, J.B.; Horton, B.L.; Zheng, Y.; Duan, Y.; Powell, J.D.; Gajewski, T.F. 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. [Google Scholar] [CrossRef]
- Zakiryanova, G.K.; Wheeler, S.; Shurin, M.R. Oncogenes in immune cells as potential therapeutic targets. ImmunoTargets Ther. 2018, 7, 21–28. [Google Scholar] [CrossRef]
- Spranger, S.; Bao, R.; Gajewski, T.F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015, 523, 231–235. [Google Scholar] [CrossRef]
- Peng, W.; Chen, J.Q.; Liu, C.; Malu, S.; Creasy, C.; Tetzlaff, M.T.; Xu, C.; McKenzie, J.A.; Zhang, C.; Liang, X.; et al. Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Discov. 2016, 6, 202–216. [Google Scholar] [CrossRef] [Green Version]
- Spranger, S.; Gajewski, T.F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 2018, 18, 139–147. [Google Scholar]
- Hamarsheh, S.; Groß, O.; Brummer, T.; Zeiser, R. Immune modulatory effects of oncogenic KRAS in cancer. Nat. Commun. 2020, 11. [Google Scholar] [CrossRef]
- Jiang, H.; Hegde, S.; Knolhoff, B.L.; Zhu, Y.; Herndon, J.M.; Meyer, M.A.; Nywening, T.M.; Hawkins, W.G.; Shapiro, I.M.; Weaver, D.T.; et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 2016, 22, 851–860. [Google Scholar] [CrossRef]
- Serrels, A.; Lund, T.; Serrels, B.; Byron, A.; McPherson, R.C.; Von Kriegsheim, A.; Gómez-Cuadrado, L.; Canel, M.; Muir, M.; Ring, J.E.; et al. Nuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity. Cell 2015, 163, 160–173. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Maeda, Y.; Nishikawa, H.; Sugiyama, D.; Ha, D.; Hamaguchi, M.; Saito, T.; Nishioka, M.; Wing, J.B.; 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. [Google Scholar] [CrossRef]
- Snyder, A.; Makarov, V.; Merghoub, T.; Yuan, J.; Zaretsky, J.M.; Desrichard, A.; Walsh, L.A.; Postow, M.A.; Wong, P.; Ho, T.S.; et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. N. Engl. J. Med. 2014, 371, 2189–2199. [Google Scholar] [CrossRef]
- Rizvi, N.A.; Hellmann, M.D.; Snyder, A.; Kvistborg, P.; Makarov, V.; Havel, J.J.; Lee, W.; Yuan, J.; Wong, P.; Ho, T.S.; et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015, 348, 124–128. [Google Scholar] [CrossRef] [Green Version]
- Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010, 363, 711–723. [Google Scholar] [CrossRef]
- Robert, C.; Thomas, L.; Bondarenko, I.; O’Day, S.; Weber, J.; Garbe, C.; Lebbe, C.; Baurain, J.-F.; Testori, A.; Grob, J.-J.; et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N. Engl. J. Med. 2011, 364, 2517–2526. [Google Scholar] [CrossRef] [Green Version]
- Fellne, C. Ipilimumab (Yervoy) prolongs survival in advanced melanoma: Serious side effects and a hefty price tag may limit its use. Pharm. Ther. 2012, 37, 503. [Google Scholar]
- Zhang, Y.; Du, X.; Liu, M.; Tang, F.; Zhang, P.; Ai, C.; Fields, J.K.; Sundberg, E.J.; Latinovic, O.S.; Devenport, M.; et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019, 29, 609–627. [Google Scholar] [CrossRef] [Green Version]
- Ji, D.; Song, C.; Li, Y.; Xia, J.; Wu, Y.; Jia, J.; Cui, X.; Yu, S.; Gu, J. Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer. J. Immunother. Cancer 2020, 8, 826. [Google Scholar] [CrossRef]
- Qu, Q.; Zhai, Z.; Xu, J.; Li, S.; Chen, C.; Lu, B. IL36 Cooperates with Anti-CTLA-4 mAbs to Facilitate Antitumor Immune Responses. Front. Immunol. 2020, 11. [Google Scholar] [CrossRef]
- Mihic-Probst, D.; Reinehr, M.; Dettwiler, S.; Kolm, I.; Britschgi, C.; Kudura, K.; Maggio, E.M.; Lenggenhager, D.; Rushing, E.J. The role of macrophages type 2 and T-regs in immune checkpoint inhibitor related adverse events. Immunobiology 2020, 225, 152009. [Google Scholar] [CrossRef]
- Sun, N.Y.; Chen, Y.L.; Lin, H.W.; Chiang, Y.C.; Chang, C.F.; Tai, Y.J.; Chen, C.A.; Sun, W.Z.; Chien, C.L.; Cheng, W.F. Immune checkpoint Ab enhances the antigen-specific anti-tumor effects by modulating both dendritic cells and regulatory T lymphocytes. Cancer Lett. 2019, 444, 20–34. [Google Scholar] [CrossRef]
- Kvarnhammar, A.M.; Veitonmäki, N.; Hägerbrand, K.; Dahlman, A.; Smith, K.E.; Fritzell, S.; Von Schantz, L.; Thagesson, M.; Werchau, D.; Smedenfors, K.; et al. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J. Immunother. Cancer 2019, 7, 103. [Google Scholar] [CrossRef] [Green Version]
- Pai, C.C.S.; Simons, D.M.; Lu, X.; Evans, M.; Wei, J.; Wang, Y.H.; Chen, M.; Huang, J.; Park, C.; Chang, A.; et al. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. J. Clin. Investig. 2019, 129, 349. [Google Scholar] [CrossRef] [Green Version]
- Morris, Z.S.; Guy, E.I.; Werner, L.R.; Carlson, P.M.; Heinze, C.M.; Kler, J.S.; Busche, S.M.; Jaquish, A.A.; Sriramaneni, R.N.; Carmichael, L.L.; et al. Tumor-specific inhibition of in situ vaccination by distant untreated tumor sites. Cancer Immunol. Res. 2018, 6, 825–834. [Google Scholar] [CrossRef] [Green Version]
- Duperret, E.K.; Wise, M.C.; Trautz, A.; Villarreal, D.O.; Ferraro, B.; Walters, J.; Yan, J.; Khan, A.; Masteller, E.; Humeau, L.; et al. Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT. Mol. Ther. 2018, 26, 435–445. [Google Scholar] [CrossRef] [Green Version]
- Tang, F.; Du, X.; Liu, M.; Zheng, P.; Liu, Y. Anti-CTLA-4 antibodies in cancer immunotherapy: Selective depletion of intratumoral regulatory T cells or checkpoint blockade? Cell Biosci. 2018, 8, 30. [Google Scholar] [CrossRef] [Green Version]
- Son, C.H.; Bae, J.; Lee, H.R.; Yang, K.; Park, Y.S. Enhancement of antitumor immunity by combination of anti-CTLA-4 antibody and radioimmunotherapy through the suppression of Tregs. Oncol. Lett. 2017, 13, 3781–3786. [Google Scholar] [CrossRef] [Green Version]
- Schwarz, C.; Unger, L.; Mahr, B.; Aumayr, K.; Regele, H.; Farkas, A.M.; Hock, K.; Pilat, N.; Wekerle, T. The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses. Am. J. Transplant. 2016, 16, 3404–3415. [Google Scholar] [CrossRef]
- Marabelle, A.; Kohrt, H.; Sagiv-Barfi, I.; Ajami, B.; Axtell, R.C.; Zhou, G.; Rajapaksa, R.; Green, M.R.; Torchia, J.; Brody, J.; et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. 2013, 123, 2447–2463. [Google Scholar] [CrossRef] [Green Version]
- Du, X.; Tang, F.; Liu, M.; Su, J.; Zhang, Y.; Wu, W.; Devenport, M.; Lazarski, C.A.; Zhang, P.; Wang, X.; et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res. 2018, 28, 416–432. [Google Scholar] [CrossRef] [Green Version]
- Sandin, L.C.; Eriksson, F.; Ellmark, P.; Loskog, A.S.I.; Tötterman, T.H.; Mangsbo, S.M. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology 2014, 3. [Google Scholar] [CrossRef] [Green Version]
- Kavanagh, B.; O’Brien, S.; Lee, D.; Hou, Y.; Weinberg, V.; Rini, B.; Allison, J.P.; Small, E.J.; Fong, L. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4 + T cells in a dose-dependent fashion. Blood 2008, 112, 1175–1183. [Google Scholar] [CrossRef] [Green Version]
- Francisco, L.M.; Salinas, V.H.; Brown, K.E.; Vanguri, V.K.; Freeman, G.J.; Kuchroo, V.K.; Sharpe, A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 2009, 206, 3015–3029. [Google Scholar] [CrossRef]
- Li, C.; Jiang, P.; Wei, S.; Xu, X.; Wang, J. Regulatory T cells in tumor microenvironment: New mechanisms, potential therapeutic strategies and future prospects. Mol. Cancer 2020, 19, 1–23. [Google Scholar] [CrossRef]
- Khan, S.; Burt, D.J.; Ralph, C.; Thistlethwaite, F.C.; Hawkins, R.E.; Elkord, E. Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation of T effector cells rather than by affecting T regulatory cells. Clin. Immunol. 2011, 138, 85–96. [Google Scholar] [CrossRef]
- Kumar, P.; Saini, S.; Prabhakar, B.S. Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis. Semin. Cancer Biol. 2020, 64, 29–35. [Google Scholar] [CrossRef]
Reference | Anti-CTLA-4 Therapy and Samples | Effect on the Presence of Treg Cells |
---|---|---|
Ji et al. 2020 [136] | In vivo investigated effect of administration of 0.25 mg anti-CTLA-4 monoclonal antibody on the CD25+Foxp3+ population in spleens and tumor tissues. | Decreased Treg cells (p < 0.05) in tumor. It did not in spleen. |
Qu et al. 2020 [137] | CTLA-4 monoclonal antibodies. | Decreased Treg cells in tumors. |
Probst et al. 2020 [138] | All patients received anti-CTLA-4 therapy and four received additional anti-PD1 therapy. | Decreased Treg cells in tumors. |
Zhang et al. 2019 [135] | In vivo anti-CTLA-4 therapy ipililumab and TremeIgG1 standard and HL12 and HL32 experimental antibodies. | Ipilimumab and TremeIgG1 downregulated cell-surface and total CTLA-4 levels in Treg cells from spleen and lung. In contrast, HL12 and HL32 had no effect on CTLA-4 level of Treg cells in the same model. |
Sun et al. 2019 [139] | In vivo anti–CTLA-4 antibody. | Downregulation of Treg cells in tumors of mice. |
Kvarnhammar et al. 2019 [140] | CTLA-4 x OX40 bispecific antibody. ATOR-1015 was used in vivo. | Reduced the frequency of Treg cells in vitro and at the tumor site in vivo. |
Sharma et al. 2019 [48] | Nineteen melanoma patient, 17 prostate cancer patient, and 9 bladder cancer patient samples were treated with ipilimumab. Eighteen melanoma tumors were treated with tremelimumab. | mAbs depleted intratumoral FOXP3+ Treg cells in tumors via Fc-dependent mechanisms. |
Pai et al. 2019 [141] | Anti CTLA-4 DVD Ig tetravalent bispecific antibody-like antibody containing an Fc region and two pairs of variable domains joined in tandem by a short flexible linker. | Decreased Treg cells in mouse tumors, but not in tissues. |
Tang et al. 2019 [144] | Anti-CTLA-4 monoclonal antibody. | Increase of Treg cells in tumors. |
Morris et al. 2018 [142] | Anti-CTLA-4 (IgG2a and IgG2b isotypes of the 9D9 clone) | Decreased Treg cells in tumors. |
Duperret et al. 2018 [143] | Anti-CTLA-4 with a TERT DNA vaccine in vivo in C57BL/6 mice. Mice were immunized at 1-week intervals for a total of four immunizations. | Decreased Treg cell frequency within the tumor. No decrease in peripheral blood. |
Du et al. 2018 [148] | In vivo anti-CTLA-4 antibodies binding to human-like ipilimumab. | Treg cell depletion. |
Son et al. 2017 [145] | Anti-CTLA-4 antibody therapy and radiotherapy in vivo. | Suppression of Treg cells in tumors. |
Schwarz et al. 2016 [146] | In vivo anti-CTLA-4 low dose (0.25 mg), high dose (1.25 mg), and very high dose (6.25 mg) were given to mice. | CD25 Treg cells were reduced independently of the doses. |
Sandin et al. 2014 [149] | In vivo comparison of low-dose peritumoral and high-dose systemic CTLA-4 blockade therapy. | As opposed to low-dose therapy, high-dose systemic therapy stimulated accumulation of Treg cells in secondary lymphoid organs. This could counteract immunotherapeutic benefit of CTLA-4 blockade. |
Marabelle et al. 2013 [147] | In vivo anti-CTLA-4 and anti-OX40 with CpG. | Depleted Treg cells in tumors. |
Sandin et al. 2010 [149] | In vivo anti-CTLA-4 or anti-PD-1 with CpG therapy. | The combinations reduced numbers of Treg cells at tumor site. |
Kavanagh et al. 2007 [150] | In vivo anti-CTLA-4 antibody dose escalation. | Increased Treg cells in tumors in a dose-dependent manner. |
Quezada et al. 2006 [47] | In vivo CTLA-4 blockade and GM-CSF combination immunotherapy mice model B16/BL6 melanoma. | Led to self-expansion of Treg cells in tumors. |
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Sobhani, N.; Tardiel-Cyril, D.R.; Davtyan, A.; Generali, D.; Roudi, R.; Li, Y. CTLA-4 in Regulatory T Cells for Cancer Immunotherapy. Cancers 2021, 13, 1440. https://doi.org/10.3390/cancers13061440
Sobhani N, Tardiel-Cyril DR, Davtyan A, Generali D, Roudi R, Li Y. CTLA-4 in Regulatory T Cells for Cancer Immunotherapy. Cancers. 2021; 13(6):1440. https://doi.org/10.3390/cancers13061440
Chicago/Turabian StyleSobhani, Navid, Dana Rae Tardiel-Cyril, Aram Davtyan, Daniele Generali, Raheleh Roudi, and Yong Li. 2021. "CTLA-4 in Regulatory T Cells for Cancer Immunotherapy" Cancers 13, no. 6: 1440. https://doi.org/10.3390/cancers13061440