The production of TGF- by stromal cells appears to be particularly relevant for the development of such phenotypes [167,168]. many functions of TGF- in T cell biology in the context of tumor immunity and discuss the possibility to manipulate Prasugrel Hydrochloride TGF- signaling to improve malignancy immunotherapy. and inhibits transcription factors is usually a cardinal feature of epithelial-mesenchymal transition (EMT), which is at the origin of the metastatic behavior of cancer cells [94,95,96]. In the case of CD8+ T cells, conditional deletion of led to low expression of the anti-apoptotic BCL-2 molecule relative to the pro-apoptotic molecule BIM in memory T cells. This is in contrast to the finding that low BCL-2 expression was proposed as a mechanism to explain the pro-apoptotic role of TGF- in effector CD8+ T cells . It is therefore likely that depending on different cellular contexts, TGF- modulates opposing cellular fates through divergent modulation of the same pathways. CD4+ T-cell differentiation. In order to mount effective immune responses, T cells must differentiate into specialized subtypes. Best described for CD4+ helper T cells , T-cell differentiation is usually heavily influenced by TGF- (Physique 1). Consistent with a predominantly immunoregulatory role and of particular relevance to T-cell responses against cancer, TGF- has been shown to significantly blunt Th1 and Th2 effector differentiation [24,43,98,99]. The CD4+ Th1 response, which overlaps with CTL differentiation in CD8+ T cells, is usually notably characterized by Prasugrel Hydrochloride IFN- production and responses against virus-infected cells and cancers. Th1 responses are significantly inhibited Prasugrel Hydrochloride by TGF-, which suppresses the expression of the Th1 fate determining transcription factors T-BET, EOMES, and STAT4 [25,43,91,99]. In addition, TGF- favors Treg differentiation from uncommitted peripheral CD4+ T cells through the induction of the Treg signature transcription factor FOXP3 [27,100,101,102,103]. Both thymus-derived and induced Tregs will suppress immune responses through several mechanisms, including the production and activation of TGF- . Along with the suppression of T-cell activation and cytotoxicity, the mitigation of Th1 responses and the induction of Treg differentiation are central to the immunoregulatory role of TGF- in tumors . The production of TGF- Prasugrel Hydrochloride by the tumor cells, immature dendritic cells, and stromal element favor the recruitment and in situ conversion of effector T cells into Tregs at least in part through the direct action of SMAD3 around the FOXP3 gene promoter [100,105,106,107,108]. Despite undisputable immunoregulatory effects, TGF- also controls T-cell differentiation programs leading to inflammatory subset generation. Among TGF–dependent subsets, Th9, Th17, and CD8+ resident memory (Trm) T cells are of particular relevance to cancer (Physique 1). Whether Th17 contributes to pro- or anti-tumor inflammation remains controversial and context-dependent (reviewed in ). Importantly, TGF- is one of the factors that may explain the dual effects of Th17 T cells in cancer. The role of TGF- in Th17 fate determination is usually both direct and indirect. Along with IL-6, IL-1, IL-23, and IL-21, TGF- directly supports the expression of the Th17 lineage determining transcription factor RORt in mouse CD4+ T cells (RORC in humans) . Moreover, the inhibition of other differentiation programs (namely, Th1 and Th2) through TGF- favors Th17 generation [111,112,113]. However, beyond the signals that initially trigger the Th17 program, several other cytokines can further specialize Th17 cells, or reverse their phenotype and function. Importantly, TGF- itself alters the Th17 fate at several stages. In addition to the cytokine context that will favor Th17 instead of Treg differentiation, a determining and often underappreciated variable is the concentration of TGF-. At high concentration, TGF- favors Treg over Th17 differentiation through inhibition of IL-23R expression and direct antagonism of FOXP3 on RORc expression . In addition, the multiplicity of signaling pathways downstream of TGF- receptors can also contribute to lineage determination. The TGF- canonical mediator SMAD4 articulates Treg but not Th17 differentiation, which was shown to rely on non-canonical AKT and MAPK signaling [48,115,116,117]. Moreover, within the context of tumors, ongoing TGF- signaling could boost several immunoregulatory properties of Th17 cells, among them, the suppression of T-BET and the expression of the ectonucleotidases CD73 and CD39 leading to adenosine production and suppression of immune responses [118,119]. Moreover, in pre-clinical models, a subset of Th17 induced by TGF- and IL-6 and expressing high levels of aryl hydrocarbon receptor (AhR) was found to secrete IL-10 and have immunoregulatory properties (Treg17) [120,121]. These data infer that the optimal mobilization of IL8RA Th17 for cancer therapy.