TGFβ1 and BMP signals modulate CD8+ T cell functionality and responsiveness to immune checkpoint blockade therapy

Abstract T cell dysfunctionality is a major challenge during chronic infections and cancer, limiting durable responses to T-cell based immunotherapies including immune checkpoint blockade (ICB). However, the role of upstream environmental signals in modulating the development of terminal dysfunction in CD8+ T cells remains to be explored. We have recently established that persistent TGFβ1 exposure drives an epigenetically stabilized, terminal dysfunction program in chronically stimulated human and mouse CD8+ T cells. In contrast, boosting BMP signaling induces a striking ability of T cells to maintain effector functionality and survival under chronic stimulation. Here, we show how rebalancing TGFβ1/BMP-signals in dysfunctional CD8+ T cells retains functionality in chronically stimulated human cord blood or tumor-infiltrating CD8+ T cells in vitro, while enhancing chronic virus or tumor control in mice. We also explore the therapeutic potential of BMP-signals in promoting durability of CD8+ T cell responses. Altogether, these findings provide an exciting new approach to enhance T cell responses to immunotherapy.