Notch-Rbpj signaling restrains regulatory T cell exhaustion in tumors

Recent efforts to characterize the immunosuppressive circuits of tumor-infiltrating Treg cells (tTreg cells), identified dysfunctional cell states including “ex Tregs”, “fragile” or metabolically-rewired Treg cells with potent anti-tumor properties; yet therapeutic targeting of Treg cells in cancer remains a major unmet need, indicating that unappreciated mechanisms of Treg cell function operate in the tumor microenvironment (TME).

A puzzling question that awaits to be addressed is why Treg cells remain functional in the hostile TME, while their lymphocytic effector counterparts become exhausted or senescent. Herein, we identified Notch-Rbpj signaling as a checkpoint pathway which hinders the induction of exhaustion in tTreg cells. Rbpj-ablated Treg cells demonstrated an exhausted-related transcriptome and chromatin landscape and exhibited increased PD1 expression which accounted for the anti-tumor immunity and inhibition of tumor development.