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.