Immunosuppressive myeloid-derived suppressor cells (MDSCs) have recently been identified as a heterogeneous cell population that expand during tumor-associated inflammation and are significantly increased in the tumor, peripheral blood, as well as ascites of ovarian cancer patients. MDSCs contribute to tumor immune tolerance via inhibition of T-cell proliferation and activation. Signals from the tumor microenvironment in the form of soluble cytokines lead to MDSC infiltration. 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 cancer cell GR expression and activity may modulate tumor cell cytokine secretion thereby leading to increased MDSC recruitment to the tumor, thereby creating an immunosuppressive environment.
Our preliminary data confirm that GR activation in high-grade ovarian cancer cell lines upregulates secretion of several immunosuppressive proteins including GCSF, TGFb, and CXCL5 in ovarian cancer models. We also observed downregulation of cytokines required for anti-tumor T-cell function including IFN-g. Importantly, treatment of cells with a selective GR modulator (SGRM) reverses this immunosuppressive secretome effect.
Upon culturing healthy peripheral blood mononuclear cells (PBMCs) with tumor conditioned media from GR activated ovarian cancer cells, we show that secreted immunomodulatory factors have the capacity to promote differentiation of human MDSCs from PBMCs. The resulting MDSC population was characterized via expression of activation markers including Arginase-1 and NOS2. Most importantly, the suppressive function of these MDSCs is being evaluated by determining their inhibitory potential on cytotoxic T-cell proliferation and/or activation. Finally, ovarian cancer xenograft models treated with a SGRM demonstrated reduced tumor infiltrated MDSCs.
We, hence, propose to determine whether targeting tumor cell-intrinsic GR activation and resulting MDSC generation has potential to improve patient outcomes in this subset of ovarian cancers.
The authors.
CPRIT.
All authors have declared no conflicts of interest.