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Unlocking the Complexities of Tumor-Associated Regulatory T Cells Jaime L

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Unlocking the Complexities of Tumor-Associated Regulatory T Cells Jaime L Unlocking the Complexities of Tumor-Associated Regulatory T Cells Jaime L. Chao and Peter A. Savage This information is current as J Immunol 2018; 200:415-421; ; of September 25, 2021. doi: 10.4049/jimmunol.1701188 http://www.jimmunol.org/content/200/2/415 Downloaded from References This article cites 48 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/200/2/415.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Unlocking the Complexities of Tumor-Associated Regulatory T Cells Jaime L. Chao and Peter A. Savage Regulatory T (Treg) cells are found at elevated densities prognostic significance (2, 3), suggesting that Treg cells may in many human cancers and are thought to be a major have a functional impact on tumor development and pro- barrier to the generation of robust antitumor T cell re- gression. Interestingly, in some cancers such as hepatocellular sponses. In this review, we discuss recent advances in the carcinoma, a high Treg cell density is predictive of poor understanding of tumor-associated Treg cell diversity clinical outcome, consistent with the paradigm that Treg cells and function. Emerging evidence indicates that the promote tumor progression by suppressing tumor-specific transcriptional program of Treg cells infiltrating human T cell responses. In contrast, a high Treg cell density is pre- cancers may represent a composite program blending a dictive of improved clinical outcome in other cancers such as Downloaded from tissue-associated expression signature with an addi- colorectal carcinoma. Although the precise mechanisms driving tional tumor-specific signature common to Treg cells this association are undefined, it has been proposed that the from multiple cancer types. Studies in mouse models favorable effect of Treg cells in colorectal carcinoma may reflect a role for Treg cells in suppressing tumor-promoting inflam- have defined unique molecular pathways required for mation in response to gut microbes (4). These disparate find- Treg cell function in the tumor context that can be ma- ings suggest that the role of Treg cells in shaping tumorigenesis http://www.jimmunol.org/ nipulated to selectively dampen intratumoral Treg cell may be highly context-dependent, varying considerably at activity. Finally, an expanding body of work has different organ sites. revealed diverse functions for Treg cells in nonlymphoid Given the pivotal role of Treg cells in immune suppression tissues that are unrelated to immune suppression, sug- and the prevalence of these cells in many human cancers, it is gesting a need to explore functions of intratumoral Treg thought that Treg cells constitute a major barrier to therapeutic cells beyond the regulation of antitumor immunity. efforts to mobilize the immune system to induce tumor re- The Journal of Immunology, 2018, 200: 415–421. gression. This idea has spurred concerted efforts to develop modalities to enhance cancer immunotherapies by inducing by guest on September 25, 2021 he development and progression of cancer can be the selective depletion or modulation of intratumoral Treg cells profoundly impacted by tumor cell–extrinsic factors while simultaneously leaving Treg cells elsewhere in the body T such as cells of the immune system, which are unaffected. In this review, we highlight recent studies that thought to either promote or restrict tumor progression in advance our understanding of tumor-associated Treg cell bi- different contexts (1). Many human tumors contain immune ology and reveal potential paths for the selective manipulation cells localized diffusely or clustered within distinct regions, of these cells. First, we discuss evidence suggesting that ther- indicative of ongoing inflammatory reactions or antitumor apeutic Abs specific for T cell–expressed receptors such as immune responses. Regulatory T (Treg) cells expressing the CTLA-4 may function in part by inducing the specific de- transcription factor Foxp3 are common protagonists in these pletion of intratumoral Treg cells. We then review recent reactions, and they are often found at elevated densities in surveys of Treg cells isolated from human tumors, which tumor lesions relative to lymphoid and nonlymphoid sites. suggest that intratumoral Treg cells are broadly imprinted by Treg cells throughout the body are essential for the prevention the tissue microenvironment, but they also express a con- of autoimmunity and the maintenance of immune homeo- served tumor-specific signature that may be common to stasis, and they function by suppressing the activation and intratumoral Treg cells from multiple cancer types. Next, we differentiation of CD4+ Th cells and CD8+ cytotoxic T cells discuss work indicating that intratumoral Treg cells require reactive to autologous, environmental, or tumor-expressed unique molecular programs to function and thrive within Ags. Numerous correlative studies have revealed that for tumor lesions, and that these programs can be selectively some cancers, the density of tumor-infiltrating Treg cells has perturbed to modulate intratumoral Treg cell activity in Department of Pathology, University of Chicago, Chicago, IL 60637 Abbreviations used in this article: ADCC, Ab-dependent cellular cytotoxicity; Areg, amphiregulin; CRC, colorectal carcinoma; cTreg, central Treg; eTreg, effector Treg; ORCID: 0000-0003-1872-734X (J.L.C.). HFSC, hair follicle stem cell; Nrp1, neuropilin-1; NSCLC, non–small cell lung cancer; Received for publication August 17, 2017. Accepted for publication October 2, 2017. Sema4a, semaphorin-4a; SLO, secondary lymphoid organ; Treg, regulatory T; VAT, visceral adipose tissue; VEGF, vascular endothelial growth factor. This work was supported by National Institutes of Health Grants R01-AI126756 (to P.A.S.) and R01-AI110507 (to P.A.S.). J.L.C. was supported by National Institutes of Health Ó Training Grant T32 AI007090. Copyright 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 Address correspondence and reprint requests to Dr. Peter A. Savage, Department of Pathology, University of Chicago, 900 E. 57th Street, KCBD 6134, Chicago, IL 60637. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701188 416 BRIEF REVIEWS: TUMOR-ASSOCIATED REGULATORY T CELLS preclinical animal models. Finally, we discuss mounting evi- Despite clear mechanistic evidence in mice that Abs can dence that Treg cells resident in nonlymphoid organs can promote tumor rejection by inducing intratumoral Treg cell function to regulate diverse processes such as tissue homeo- depletion, the relevance of these concepts to the efficacy of Ab- stasis, repair, and metabolism, and we speculate about the based immunotherapies in human cancer patients remains potential implications of these findings on our understanding undefined. The clearest available evidence in support of this of tumor-associated Treg cells. We conclude by highlighting idea comes from the studies of Romano et al. (14), which critical gaps in knowledge in the field and outlining future compared samples from human melanoma patients who did inquiries needed to gain a more complete understanding of or did not respond to therapy using the anti–CTLA-4 Ab intratumoral Treg cells at different organ sites. ipilimumab. In ex vivo assays, it was found that nonclassical monocytes expressing the activating Fc receptor CD16 can Do “checkpoint blockade” Abs function by depleting intratumoral engage ipilimumab and induce ADCC-mediated lysis of Treg Treg cells? cells in vitro. Importantly, clinical responses to ipilimumab In the past decade, Abs specific for the T cell coinhibitory were associated with Treg cell depletion in tumor lesions, as receptors CTLA-4 and PD-1 have shown striking success in well as elevated densities of nonclassical monocytes in the inducing durable clinical benefit in a fraction of cancer patients peripheral blood at baseline compared with nonresponders spanning a variety of cancer types (5). Early in their devel- (14), suggestive of ADCC-dependent intratumoral Treg cell opment, these Abs were dubbed “checkpoint blockade” Abs ablation. Taken together, the studies above support the idea based on the idea that they were thought to function by that Abs specific for T cell–expressed receptors may function in Downloaded from blocking the binding of CTLA-4 or PD-1 to their ligands, part by inducing the selective elimination of tumor-infiltrating thereby releasing tumor-specific T cells from checkpoints, Treg cells in circumstances in which the Ab isotype can avidly limiting their activation and effector function (6). However, engage activating Fc receptors, and Fc receptor–expressing
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