IL-33 drives polyfunctionality and antitumor activity of a unique ST2+ NK cell population
Eberhardt, A.; Blanc, E.; Picant, V.; Alcazer, V.; Rocca, Y.; Ardin, M.; Voissiere, A.; Onodi, F.; Rodriguez, C.; Tonon, L.; Estavoyer, B.; Moudombi, L.; Charrier, E.; Wang, X.; Stojanovic, A.; Rau, T.; Tredan, O.; Treilleux, I.; Michallet, M.-C.; Valladeau-Guilemond, J.; Marcais, A.; Walzer, T.; Krebs, P.; Cerwenka, A.; Hubert, M.; Caux, C.; Bendriss-Vermare, N.
Show abstract
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-{gamma} in response to IL-33 and IL-33/IL-12 co-injection resulted in a NK-dependent IFN-{gamma} 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. One sentence summaryThe IL-33/IL-33R(ST2)/NK cell axis is a key determinant of cancer immunity and immunotherapy.
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