Abstract
Elevated levels of IL-10 in the microenvironment of human ovarian cancer and murine models of ovarian cancer are well established and correlate with poor clinical prognosis. However, amongst a myriad of immunosuppressive factors, the actual contribution of IL-10 to the ovarian tumor microenvironment, the mechanisms by which it acts, and its possible functional redundancy are unknown. We previously demonstrated that elimination of the myeloid-derived suppressor cell (MDSC) compartment within the ovarian tumor ascites inhibited tumor progression and, intriguingly, significantly decreased local IL-10 levels. Here we identify a novel pathway in which the tumor-infiltrating MDSC are the predominant producers of IL-10 and, importantly, require it to develop their immunosuppressive function in vivo. Importantly, we demonstrate that the role of IL-10 is critical, and not redundant with other immunosuppressive molecules, to in vivo tumor progression: blockade of the IL-10 signaling network results in alleviation of MDSC-mediated immunosuppression, altered T cell phenotype and activity, and improved survival. These studies define IL-10 as a fundamental modulator of both MDSC and T cells within the ovarian tumor microenvironment. Importantly, IL-10 signaling is shown to be necessary to the development and maintenance of a permissive tumor microenvironment and represents a viable target for anti-tumor strategies.
Highlights
Ovarian cancer is characterized by a progressive peritoneal ascites and a highly immunosuppressive tumor microenvironment infiltrated by massive numbers of leukocytes
The CD11b+ compartment in the ascites, which we have previously identified as functional myeloid-derived suppressor cell (MDSC) (Bak et al, 2008; Hart et al, 2009), robustly expressed the reporter and represented the vast majority of the cells that stained positive for the reporter, and make up the bulk of the total leukocyte infiltrate (Figures 1C,D)
We demonstrate that IL-10 production by MDSCs, and MDSC responsiveness to IL-10, plays a critical role in the failure of the immune system to control ovarian tumor growth, resulting from a breakdown in multiple integral components required for effective anti-tumor immunity
Summary
Ovarian cancer is characterized by a progressive peritoneal ascites and a highly immunosuppressive tumor microenvironment infiltrated by massive numbers of leukocytes. Amongst a plethora of known immunosuppressive factors within this tumor microenvironment, including arginase, TGF-β, and PD-L1, IL-10 has generated a great deal of interest. IL-10 has numerous suppressive functions involved in dampening inflammatory responses of the immune system, including inhibition of myeloid cell maturation and reduction of expression of co-stimulatory molecules on dendritic cells (Moore et al, 2001). The exact roles IL-10 plays in the ovarian tumor microenvironment and which of these directly contribute to the support of tumor progression are unknown. Given the multitude of potentially redundant immunosuppressive factors present, how the IL-10 signaling networks function and contribute within the peritoneal ovarian tumor microenvironment is currently unclear
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