TGF-β in T Cell Biology: Implications for Cancer Immunotherapy

Abstract

Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy.

Keywords: T cells; TGF-β; cancer; immunotherapy.

Figure 1

Overview of TGF-β effects on T-cell subsets. Graphical representation of positive (green) or inhibitory (red) effects of TGF-β signaling on T-cell differentiation across developing T cells (in the thymus, light blue) or mature T-cell subsets (in the periphery, dark blue). Mechanistic or physiologic impact of TGF-β signaling on the various T-cell subsets indicated in the white boxes).

Figure 2

Schematic representation of TGF-β as a modulator of the tumor microenvironment. Representation of inflammatory lymphoid and myeloid (DC-dendritic cells, M1 inflammatory macrophages, or neutrophils—N1) immune cells was negatively regulated (red) by TGF-β, and anti-inflammatory subsets were promoted (green) by the actions of TGF-β (including myeloid-derived suppressor cells-MDSC, anti-inflammatory macrophages—M2 or neutrophils—N2). The action of TGF-β in the migration and retention of T cells is exemplified by the effect on Trm differentiation and can result in both tumor infiltrating lymphocyte (TIL) generation or lead to exclusion from tumors when TGF-β is produced by surrounding stromal cells.