Notch-Rbpj signaling restrains regulatory T cell exhaustion in tumors

Regulatory T cells (Treg cells) are vital for immune homeostasis and prevention of autoimmunity while they exert an essential role in promoting tumor development. 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. In support, PD1 deletion in exhausted Treg cells, rescued their exhausted phenotype and reinvigorated their tumor-promoting function. Finally, therapeutic administration of novel small molecule Rbpj inhibitors promoted Treg cell exhaustion and tumor reduction. Our findings suggest the Notch-Rbpj axis as an immune checkpoint for Treg cell exhaustion which could be targeted therapeutically for cancer therapy.