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. Herein, we identify a cell-intrinsic role of the alarmin 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 an ST2 (IL-33 receptor)-independent fashion. Upon activation, Il33(–/–) T(reg) cells exhibited epigenetic reprogramming with increased chromatin accessibility of the Ifng locus leading to elevated interferon-γ (IFN-γ) production in an NF-κB–T-bet-dependent manner. IFN-γ was essential for T(reg) cell defective function since its ablation restored Il33(–/–) T(reg) cell suppressive properties. Importantly, genetic ablation of Il33 potentiated the therapeutic effect of immunotherapy. Our findings reveal a novel and therapeutically important intrinsic role of IL-33 in T(reg) cell stability in cancer.