Santana Carrero et al. show that the soluble IL-15/IL-15Rα complex (sIL-15) was abundant in early tumors and was required in combination with type I IFN for lymphocyte infiltration, but declined as tumors matured. sIL-15 was produced primarily by myeloid cells and sometimes by tumor cells or non-hematopoietic cell types. In established tumors, sIL-15 was low, but IL-15-expressing myeloid cells were abundant, and intratumoral STING agonism increased sIL-15 release. STING agonism also increased cytolytic cell proliferation in secondary lymphoid organs and mediated regression of injected and distal tumors, which was dependent on IL-15.
Previous studies have provided evidence that IL-15 expression within human tumors is crucial for optimal antitumor responses; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. We report herein, in analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15Ralpha complexes (sIL-15 complexes) are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes. Moreover, IL-15 as well as type I IFN, which regulates IL-15, was required for establishing normal numbers of CD8 T cells and natural killer cells in tumors. Depending on tumor type, both the tumor and the stroma are sources of sIL-15 complexes. In analyses of IL-15 reporter mice, most myeloid cells in the TME express IL-15 with CD11b(+)Ly6C(hi) cells being the most abundant, indicating there is a large source of IL-15 protein in tumors that lies sequestered within the tumor stroma. Despite the abundance of IL-15-expressing cells, the relative levels of sIL-15 complexes are low in advanced tumors but can be up-regulated by local stimulator of IFN genes (STING) activation. Furthermore, while treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. Overall, our study reveals the dynamic regulation of IL-15 in the TME and its importance in antitumor immunity. These findings provide insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity, which can be manipulated therapeutically to enhance antitumor responses.