IL-33 drives polyfunctionality and antitumor activity of a unique ST2+ NK cell population

Natural Killer (NK) cell subsets differ to ensure complementary and crucial roles in tumor immunosurveillance. Their biology is critically regulated by cytokines. Here, we show that IL-33 synergizes with IL-12 to strongly activate a subset of CD56dim NK cells acquiring ST2 expression. Transcriptomic and biological analysis of human ST2+ CD56dim NK cells revealed a distinct intermediate differentiation state between canonical CD56bright and CD56dim NK cells, combining high proliferative properties, cytokines/chemokines production, and cytotoxicity. NK cells expressing ST2 protein or exhibiting a ST2-linked transcriptional signature were identified in human and mouse tumors. Accordingly, IL-12 unleashes human breast tumor ST2+ NK cell potential to produce IFN-γ in response to IL-33 and IL-33/IL-12 co-injection resulted in a NK-dependent IFN-γ secretion and anti-tumor effects in murine mammary tumors. An IL33hi-NKhi score in solid tumors correlated with increased progression-free patient survival. Our findings thus identify polyfunctional ST2+ NK cells which effector functions can be harnessed by IL-33 to boost anti-tumor immunity. ### Competing Interest Statement The authors have declared no competing interest.