An intrinsic role of IL-33 in T reg cell–mediated tumor immunoevasion

Regulatory T (T reg ) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of T reg cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide T reg cell stability in tumors remain elusive. In the present study, we identify a cell-intrinsic role of the alarmin interleukin (IL)-33 in the functional stability of T reg cells. Specifically, IL-33-deficient T reg cells demonstrated attenuated suppressive properties in vivo and facilitated tumor regression in a suppression of tumorigenicity 2 receptor (ST2) (IL-33 receptor)-independent fashion. On activation, Il33 −/− T reg cells exhibited epigenetic re-programming with increased chromatin accessibility of the Ifng locus, leading to elevated interferon (IFN)-γ production in a nuclear factor (NF)-κB–T-bet-dependent manner. IFN-γ was essential for T reg cell defective function because its ablation restored Il33 −/− T reg cell-suppressive properties. Importantly, genetic ablation of Il33 potentiated the therapeutic effect of immunotherapy. Our findings reveal a new and therapeutically important intrinsic role of IL-33 in T reg cell stability in cancer.