Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

cancers Review Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting? Pierre Stéphan y , Raphaëlle Lautraite y, Allison Voisin and Yenkel Grinberg-Bleyer * Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008 Lyon, France; [email protected] (P.S.); [email protected] (R.L.); [email protected] (A.V.) * Correspondence: [email protected]; Tel.: +33-(0)-469-856-248 These authors contributed equally to this paper. y Received: 9 October 2020; Accepted: 28 October 2020; Published: 30 October 2020 Simple Summary: Cancer outcomes are often indexed to the quality of the immune response to the tumor. Among immune cells, Foxp3+ regulatory T cells (Treg cells) are potent inhibitors of cancer immunity, and their presence within solid tumors is generally associated with a poor prognosis. Thus, understanding how Treg cell identity is controlled, is of utmost importance for the development of novel anti-cancer therapies. In this review, we summarize the current knowledge on the different intracellular pathways involved in the programming of Treg cell homeostasis and functions in cancer. We also highlight the therapeutic approaches aiming at targeting these regulators to enhance anti-tumor immunity. Abstract: Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators. Keywords: regulatory T cells; cancer; transcription; immunotherapy 1. Introduction Forkhead Box Protein P3 (Foxp3)+ regulatory T (Treg) cells compose 5–20% of the total CD4+ T cell pool. Their primary and most described function is to maintain immune tolerance and prevent autoimmunity at all time [1]. This is illustrated by the systemic autoimmune syndrome observed in Scurfy mice and Immunodysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) patients who carry mutations in Foxp3 and after the ablation of Treg cells in young and adult mice [2–5]. In addition, through their multiple mechanisms of suppression, Treg cells are involved in the inhibition of a wide variety of immune responses, ranging from infection to cancer immunity [6]. Studies conducted in preclinical murine models have established the deleterious function of Treg cells in cancer. Indeed, Cancers 2020, 12, 3194; doi:10.3390/cancers12113194 www.mdpi.com/journal/cancers Cancers 2020, 12, x 2 of 20 Cancerscancer.2020 Indeed,, 12, 3194 genetic and antibody-mediated depletion of Treg cells enhances tumor immunity2 ofand 20 reduces tumor burden in many settings [7,8]. These conclusions have been largely confirmed in cancer patients, where the accumulation of Treg cells in the blood and tumor tissues is generally geneticindicative and of antibody-mediated poor prognosis, depletionthough several of Treg exceptions, cells enhances such tumor as colorectal immunity cancer, and reduces have tumor been burdenidentified in [9] many. Because settings of this [7,8 ].deleterious These conclusions facet, the havedevelopment been largely of therapies confirmed aiming in cancer at modulating patients, whereTreg recruitment, the accumulation accumulation of Treg, cellsand function in the blood in the and tumor tumor microenvironment tissues is generally is an indicative area of extensive of poor prognosis,investigation though in the several fieldexceptions, of cancer suchimmunotherapy. as colorectal cancer,As a prominent have been identifiedexample, [9anti]. Because-Cytotoxic of this T- deleteriousLymphocyte facet,-Associated the development Protein 4 of (CTLA therapies-4) aimingantibodies, at modulating the first approved Treg recruitment, checkpoint accumulation,-blockade andtherapy function for cancer, in the tumorwere shown microenvironment to exert their is beneficial an area of effects extensive in cancer investigation by decreasing in the field Treg of cells cancer in immunotherapy.mouse models [10] As, athough prominent the relevance example, anti-Cytotoxicof this mechanism T-Lymphocyte-Associated in patients is still under Protein debate 4 (CTLA-4) [11,12]. antibodies,The effect of the Programmed first approved Death checkpoint-blockade-1 (PD-1) blockade on therapy Treg cells for cancer,and its contri werebution shown to to therapeutic exert their beneficialefficacy is ealsoffects under in cancer scrutiny by decreasing (reviewed Tregin [13] cells). Interestingly, in mouse models it was [10 suggested], though that the relevance PD-1 inhibition of this mechanismon Treg cells in may patients contribute is still underto the debatehyperprogressive [11,12]. The disease effect of observed Programmed in a number Death-1 of (PD-1) patients blockade with ongastric Treg cancer cells and [14] its. contributionTogether, this to therapeuticdemonstrates effi cacythe iscentral also under role scrutinyof Treg (reviewed cells in incancer [13]). Interestingly,immunotherapy. it was Cutting suggested-edge that technologies PD-1 inhibition now onprovide Treg cells scientists may contribute with the toability the hyperprogressive to comprehend diseasethe complexity observed of in Treg a number cell populations of patients withand gastrictheir molecular cancer [14 regulation]. Together, to this highlight demonstrates additional the centraltherapeutic role oftargets. Tregcells in cancer immunotherapy. Cutting-edge technologies now provide scientists with the ability to comprehend the complexity of Treg cell populations and their molecular regulation to2. An highlight Overview additional of Treg therapeutic Cell Subsets targets. and Their Transcriptional Regulation 2. AnThe Overview existence of of Treg different Cell Subsets flavors of and Treg Their cells Transcriptional underlies their Regulationlarge panel of functions. First, Treg cells can either develop in the thymus (tTreg) or differentiate in peripheral lymphoid tissues from naïveThe conventional existence of (Tconv) different cells flavors (pTreg of Treg cells cells and underlies their i theirn vitro large relatives, panel of iTreg). functions. To First,date, Tregwhether cells canthese either two developpopulations in the rely thymus on shared (tTreg) or ordistinct differentiate transcription in peripheral factor activity lymphoid remains tissues unclear. from naïve The conventionalproper development (Tconv) cellsof Treg (pTreg cells cells relies and on their a largein vitro numberrelatives, of iTreg).transcriptional To date, and whether epigenetic these tworegulators, populations either rely for on their shared survival or distinct or for transcription the expression factor of activity Foxp3 remains or its unclear.stabilization. The properThese developmentmechanisms have of Treg been cells largely relies ondeciphered a large number elsewhere of transcriptional [15,16], and andwe will epigenetic therefore regulators, focus our either review for theiron the survival transcriptional or for the regulation expression of ofmature Foxp3 Foxp3 or its+ stabilization. Treg cells. These mechanisms have been largely decipheredTreg cell elsewhere subsets can [15, 16also], andbe defined we will b thereforeased on their focus activation our review status. on the W transcriptionalhereas naïve-like regulation Resting + ofcells mature (rTreg) Foxp3 are primarilyTreg cells. found in lymphoid tissues, engagement of the T-Cell Receptor (TCR) and its coTreg-stimulation cell subsets partner can also CD28, be defined as well based as onmembers their activation of the Tumor status. WhereasNecrosis naïve-likeFactor Receptor Resting cellsSuperFamily (rTreg) are (TNFRSFs), primarily founddrives in the lymphoid maturation tissues, of engagement rTreg cellsof to the a T-Cellhighly Receptor immunosuppressive (TCR) and its co-stimulationActivated subset partner (aTreg CD28, cells, as also well known as members as effector of the eTr Tumoreg cells) Necrosis [17].Factor aTreg Receptorcells migrate SuperFamily to non- (TNFRSFs),lymphoid tissues, drives thewhere maturation they maintain of rTreg tissue cells tohomeostasis a highly immunosuppressive and potently suppress Activated ongoing subset immune (aTreg cells,responses. also known In particular, as effector aTreg eTreg cells cells) are highly [17]. aTreg abundant cells migratein the tumor to non-lymphoid microenvironment tissues, and where express they maintaina large panel tissue of im homeostasismune checkpoints and potently (i.e., inhibitory

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