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 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-γ secretion and anti-tumor effects in murine mammary tumors. An IL33 hi -NK hi 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. One sentence summary The IL-33/IL-33R(ST2)/NK cell axis is a key determinant of cancer immunity and immunotherapy.