Ovarian cancer cell glucocorticoid receptor activity modulates cytokine secretion promoting infiltration of immunosuppressive cells into the tumor microenvironment

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) have been identified as a heterogeneous cell population that expand during tumor progression and infiltrate the tumor, peripheral blood, as well as ascites of ovarian cancer patients. MDSCs contribute to tumor immune tolerance via inhibition of T-cell proliferation/activation. It is also known that high tumor cell glucocorticoid receptor (GR) expression is associated with a relatively poor prognosis in ovarian cancer patients. We hypothesized that ovarian tumor cell GR expression and activity may modulate tumor cell cytokine secretion thereby leading to increased MDSC generation and recruitment, thus creating an immunosuppressive tumor microenvironment. Our preliminary data confirms GR-mediated secretion of pro-tumorigenic cytokines including G-CSF, TGF-b, and MCP-1 in high-grade ovarian cancer models. We also observed GR-mediated downregulation of IL-2 and IFN-g, cytokines required for anti-tumor T-cell function. Importantly, treatment of cells with a competitive GR antagonist reversed this immunosuppressive secretome effect. Moreover, culturing healthy peripheral blood mononuclear cells (PBMCs) with tumor conditioned media from GR activated ovarian cancer cells demonstrated that secreted immunomodulatory factors have the capacity to promote differentiation of human MDSCs from PBMCs. Based on the insight provided by these data, we propose to determine whether ovarian tumor cell-intrinsic GR activation and resulting MDSC generation has an inhibitory effect on cytotoxic T-cell function, contributing to earlier relapse of GR-positive ovarian cancers, and eventually whether this mechanism may be targeted to improve patient outcomes in this subset of ovarian cancers. Supported by grant from CPRIT