Trans-Presentation of IL-15 by IL15Rα Attenuates Tumor Immune Surveillance and Is Dispensable for IL-15-Dependent Tumor Growth Control

Background: IL-15 is a promising cytokine for cancer immunotherapy. IL-15 promotes differentiation and homeostasis of innate and adaptive immune cells, and their cytolytic effector functions. The IL-15 receptor is composed of IL-15Rα, IL-15Rβ and the common γc chains. IL-15 is also trans-presented as IL-15Rα:IL-15 complex to IL-15Rβ:γc on neighboring cells. IL-15Rα is dispensable for early immune response to infections and in autoimmune diabetes. The role of IL-15Rα in antitumor immune responses remains unclear. Methods: In WT, Il15−/− and Il15ra−/− mice, we studied the growth of syngeneic tumor cell lines and tumor immune surveillance against endogenous fibrosarcoma induced by methylcholanthrene (MCA). Immune gene signature and total proteome analysis were performed on MCA-induced tumors. Results: Lack of IL-15 or IL-15Rα did not enhance the growth of implanted tumor cell lines, despite reduced immune cell infiltration. MCA-induced tumor incidence was reduced in mice lacking IL-15Rα but not IL-15, although both are required for efficient tumor immunoediting. Il15−/− and Il15ra−/− tumors showed reduced Ifng expression but displayed differential modulation of Ifng-responsive genes. Proteome profiles of Il15−/− tumors, but not tumor-derived cell lines, showed significant reduction in antigen presentation pathways. B16-F10 melanoma cells expressing NLRC5, the IFNγ-induced transcriptional activator of tumor antigen presentation, still required IL-15 but not IL-15Rα for efficient tumor control. Conclusions: Our findings show that IL-15 plays a negligible role in immunosurveillance against spontaneous tumor development, whereas IL-15Rα restrains immunosurveillance. Neither IL-15 nor IL-15Rα have a significant impact on implanted tumor models, although IL-15 facilitates efficient control of highly immunogenic tumors for which IL-15Rα is dispensable.