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

ARTICLE EN REVISION FAVORABLE DANS SCIENCE IMMUNOLOGYNatural 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 CD56 dim NK cells acquiring ST2 expression. Transcriptomic and biological analysis of human ST2 + CD56 dim NK cells revealed a distinct intermediate differentiation state between canonical CD56 bright and CD56 dim 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- secretion and anti-tumor effects in murine mammary tumors. An IL33 hi-NK hi score in solid tumors correlated with increased progressionfree patient survival. Our findings thus identify polyfunctional ST2 + NK cells which effector functions can be harnessed by IL-33 to boost anti-tumor immunity