An intrinsic role of IL-33 in Treg 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)-. production in a nuclear factor (NF)-kappa B-T-bet-dependent manner. IFN-gamma 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.