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Apoptotic Regulatory T Cells Retain Suppressive Function through Adenosine

2018; Cell Press; Volume: 27; Issue: 1 Linguagem: Inglês

10.1016/j.cmet.2017.12.013

1932-7420

Ulf H. Beier,

Immunotherapy and Immune Responses

Regulatory T cells maintain tolerance and prevent autoimmunity, but their suppressive effects can hinder immune responses against cancer. In Nature Immunology, Maj et al., 2017Maj 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: 1332-1341Crossref PubMed Scopus (388) Google Scholar report that regulatory T cells can execute these actions through the nucleoside adenosine even after cell death. Regulatory T cells maintain tolerance and prevent autoimmunity, but their suppressive effects can hinder immune responses against cancer. In Nature Immunology, Maj et al., 2017Maj 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: 1332-1341Crossref PubMed Scopus (388) Google Scholar report that regulatory T cells can execute these actions through the nucleoside adenosine even after cell death. Foxp3+ regulatory T cells (Tregs) are capable of restricting undesired immune responses against self-antigens, allergens, and commensal bacteria. Beyond these important physiologic functions, Tregs can also become an obstacle to beneficial immune responses, especially in the context of cancer. Tregs are often found enriched in the tumor microenvironment (TME) of solid cancers and help the tumor evade host immunity. Understanding how Tregs function in the TME is important to improve anti-tumor immunotherapy. Among the recognized mechanisms of Treg-mediated suppression are direct cell-cell contacts with inhibitory surface molecules, consumption of ambient IL-2 to deprive its use by other T cells, and secretion of inhibitory cytokines and other mediators such as IL-10, IL-35, transforming growth factor-β, and granzyme B. In general, these suppressive mechanisms require viable Tregs with intact gene transcription and translation. Maj et al. now report that many Foxp3+ T cells in the TME of human ovarian cancer have entered apoptotic cell death at a much higher rate than Foxp3− T cells (Maj et al., 2017Maj 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: 1332-1341Crossref PubMed Scopus (388) Google Scholar), raising questions of whether Tregs are more prone to become apoptotic and whether apoptotic Tregs are still capable of immunosuppression. Maj et al., 2017Maj 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: 1332-1341Crossref PubMed Scopus (388) Google Scholar isolated viable T cells from human ovarian tumors, induced apoptosis by activating CD95, and observed that apoptotic Tregs, but not conventional T cells, had potent immunosuppressive function even surpassing that of live Tregs. The authors made similar observations with murine Tregs isolated from the TME of MC38 colon carcinomas. Apoptotic Tregs showed strong suppressive effects in vivo, negating the therapeutic benefits of antibodies against programmed death-ligand-1 (PD-L1), and adoptively transferred tumor-antigen-specific T cells against MC38 carcinomas and B16-F10 melanomas, respectively. Mechanistically, the authors observed that TME Tregs are prone to apoptosis due to impaired nuclear factor (erythroid-derived 2)-like 2 (NRF2) mRNA, protein, and transcriptional activity, resulting in decreased protection from reactive oxygen species (ROS), which is enriched in the TME. This results in cell membrane damage and eventually cell death (Figure 1). Subsequently, adenosine triphosphate (ATP) released from the dying Treg undergoes dephosphorylation via CD39 and CD73, generating adenosine in the process, which then binds to the adenosine A2A receptor (A2AR). The A2AR is expressed on antigen-presenting cells as well as effector and cytotoxic T cells and, upon adenosine binding, activates immunosuppressive signals (Figure 1). The observation that apoptotic Tregs remain capable of strong immunosuppression has several important implications. First and foremost, it raises the question of whether killing Tregs in the TME should remain a therapeutic strategy to improve anti-tumor immunity. Could antibodies targeting Tregs, under the wrong circumstances, be ineffective or even counterproductive to this goal? This is an important point to consider, since some therapeutic antibodies are aimed at killing Tregs (chemokine receptor type-4, CCR4) or increase Treg apoptosis (cytotoxic T-lymphocyte protein-4, CTLA4). Both are undergoing clinical trials and with only modest success (Kurose et al., 2015Kurose 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: 4327-4336Crossref PubMed Scopus (157) Google Scholar, Maio et al., 2017Maio M. Scherpereel A. Calabrò L. Aerts J. Perez S.C. Bearz A. Nackaerts K. Fennell D.A. Kowalski D. Tsao A.S. et al.Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.Lancet Oncol. 2017; 18: 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). Of note, early attempts to deplete immunoregulatory T cells in murine tumor models with CD25 antibodies were effective only if administered prior to, but not at > 2 days after, tumor cell inoculation (Onizuka et al., 1999Onizuka 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: 3128-3133PubMed Google Scholar). Back then, this observation was attributed to the expression of CD25 in activated T cells. However, with the new results from Maj et al., it is tempting to speculate if Treg apoptosis also plays a role in this outcome. Perhaps destabilizing rather than killing Tregs (Overacre-Delgoffe et al., 2017Overacre-Delgoffe A.E. Chikina M. Dadey R.E. Yano H. Brunazzi E.A. Shayan G. Horne W. Moskovitz J.M. Kolls J.K. Sander C. et al.Interferon-gamma drives treg fragility to promote anti-tumor immunity.Cell. 2017; 169: 1130-1141.e11Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar) and/or making tumor-infiltrating effector T cells resistant to the TME (Scharping et al., 2016Scharping N.E. Menk A.V. Moreci R.S. Whetstone R.D. Dadey R.E. Watkins S.C. Ferris R.L. Delgoffe G.M. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction.Immunity. 2016; 45: 374-388Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar) may be more promising therapeutic approaches to avoid unintentionally augmenting immunosuppression through Treg apoptosis. Based upon the data from the Maj et al. paper, it will be necessary to carefully evaluate if therapies inducing Treg apoptosis could have diminished or adverse effects through augmented immunosuppression from apoptotic Tregs. Beyond cancer, this mechanism observed by Maj et al. could also be relevant to other pathophysiological conditions. Apoptotic Tregs could serve as a guard against developing autoimmunity when intracellular antigens not covered by thymic selection are exposed during an extended ischemia-reperfusion injury, as well as in other challenging, pro-apoptotic environments when self-sensitization needs to be avoided. As many outstanding papers do, the study by Maj et al. also raises several new questions. For example, if Tregs are more vulnerable to ROS and prone to apoptosis, how do they remain such a prominent population in the TME and not undergo a faster rate of turnover than invading conventional T cells? Effector and cytotoxic T cells are particularly vulnerable to the absence of glucose and glutamine (Chang et al., 2015Chang C.H. Qiu J. O’Sullivan D. Buck M.D. Noguchi T. Curtis J.D. Chen Q. Gindin M. Gubin M.M. van der Windt G.J. et al.Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell. 2015; 162: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (1680) Google Scholar, Johnson et al., 2016Johnson M.O. Siska P.J. Contreras D.C. Rathmell J.C. Nutrients and the microenvironment to feed a T cell army.Semin. Immunol. 2016; 28: 505-513Crossref PubMed Scopus (42) Google Scholar) as well as the presence of lactic acid (Brand et al., 2016Brand A. Singer K. Koehl G.E. Kolitzus M. Schoenhammer G. Thiel A. Matos C. Bruss C. Klobuch S. Peter K. et al.LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.Cell Metab. 2016; 24: 657-671Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar), all conditions that Tregs can sustain better than effector and cytotoxic T cells (Angelin et al., 2017Angelin A. Gil-de-Gomez L. Dahiya S. Jiao J. Guo L. Levine M.H. Wang Z. Quinn 3rd, W.J. Kopinski P.K. Wang L. et al.Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments.Cell Metab. 2017; 25: 1282-1293.e7Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar). With these vulnerabilities of conventional T cells on one hand and increased ROS susceptibility of Tregs reported by Maj et al. on the other, future studies will be needed to determine which cell population is better adapted to the harsh metabolic conditions of the TME. The high rate of apoptosis seen in the Foxp3+ T cells in human ovarian cancer may also represent some conventional T cells, as Foxp3 can be expressed in activated human effector T cells. If that is the case, are Foxp3+ effector T cells also more vulnerable to ROS-induced apoptosis? Is Foxp3 regulating NRF2 expression or signaling, or another regulator determining NRF2 turnover? Notably, NRF2 protein is subject to post-translational control through Keap1, which binds NRF2, keeping it from nuclear translocation (Figure 1), and aids in its proteasomal degradation. A lower NRF2 protein level and NRF2-dependent gene transcription does therefore not rule out a more basal state with less ROS challenge and NRF2 release from Keap1. Taken together, the findings presented by Maj et al. are a crucial step forward in understanding the role of Tregs in the TME and may also point to a novel physiologic mechanism of Treg-mediated peripheral tolerance. The observation that apoptotic Tregs can have potent immunosuppressive function will have far-reaching implications for cancer immunotherapy.