IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses

Abstract

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-15Rα 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+Ly6Chi 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.

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

“…In contrast, numbers of immune-suppressing cells such as T reg cells, myeloid-derived suppressor monocytes and M2 macrophages have been reported to be decreased (225,238,239). Expression of IL-15/IL-15Rα complex is up-regulated in myeloid cells with the help of STING/type-I IFN and promotes tumor regression (240).…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Interestingly, TUSC2 modulated the TME to facilitate homing and altered the infiltrating immune populations through an increase of IL-15 and of the chemo-attractants Ccl3/4. This is especially important due to low NK cell infiltration and proliferation in solid tumors, and may open avenues for targeting tumor suppressor genes to increase IL-15 in the tumor bed, since its expression by the pro-inflammatory milieu in tumors was recently shown to play a critical role in NK cell infiltration and activation (304). TUSC2 treatment promoted the survival of mice in the lung metastasis model, and synergized with conventional anti-PD1/CTLA-4 therapy (305).…”

Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial

“…Pattern-recognition receptors (PRR) are proteins expressed by immune cells that recognize pathogenassociated molecular patterns as danger signals [95,96]. IL6, IL8, and TNFα are produced in response to PRR that trigger a response from NK cells that is associated with production of IL15, IL18, and IFNγ [14][15][16][17]. Cytokines that regulate innate immunity are produced primarily by mononuclear phagocytes such as macrophages and DCs, although they can also be produced by T-lymphocytes, natural killer (NK) cells, endothelial cells, and mucosal epithelial cells.…”

“…Inducing new immune responses, or enhancing existing weak immune responses to cancer associated antigens, is the goal of anti-cancer vaccines [12,13]. Innate immunity features natural killer cells and associated cytokines [14][15][16][17], and macrophages which also produce cytokines and their function is affected by cytokines [18][19][20][21]. Adaptive immunity includes Th1 cell-mediate immunity and Th2 humoral immunity [22].…”