Context- and subset-dependent activation of NK cells by interleukin-33 in tumors
PICANT V. 1, REVOL-BAUZ L. 1, VOISSIERE A. 1, ROCCA Y. 1, EBERHARDT A. 1, POUJOL D. 1, CAUX C. 1, BENDRISS-VERMARE N. 1
1 Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, F-69000 Lyon, France, Lyon, France
Natural Killer (NK) cells are key players in cancer immunosurveillance by directly killing tumor cells and supporting effective antitumor immune responses. However, they get progressively dysfunctional in developing tumors. A promising strategy consists in the identification of soluble factors or surface receptors that drive the activation and anti-tumor function of NK cells. The stress-induced alarmin Interleukin-33 (IL-33) activates NK in infectious models while its role in tumor contexts remains unclear. Based on the team's previous results, we hypothesized that the IL-33/IL-33R axis is a novel pathway for NK activation during tumor immunosurveillance and we investigated the activating potential of the IL-33 cytokine on healthy donors and cancer patients NK cells.
First, we highlighted the importance of the dendritic cells (DC)/NK crosstalk in the IL-33R induction, with a major role of conventional DC-derived cytokines. Moreover, we observed that IL-12 and IL-15 differentially regulated IL-33R expression on NK cell subpopulations leading to cytotoxicity, cytokine secretion, and proliferation in response to IL-33. RNAseq analysis reinforced that IL-33 effect is context- and NK cell subset-specific. Furthermore, NK cells isolated from various tumor types were still able to produce IFN-γ in response to IL-33 combined to IL-12 and/or IL-15 ex vivo. Using in vivo tumor models, we reported that IL-33 synergizes with DC-activating TLR agonists to limit tumor development in therapeutic settings. Finally, we observed a higher tumor growth rate in IL33KO mice compared to wild type mice, highlighting a role for IL-33 in cancer immune surveillance.
Thus, our work identifies IL-33 as a context- and subset-dependent NK cell activator that might be used to reverse intratumor NK cell dysfunctionality, paving the way to a refinement of immunotherapies targeting innate cells.