Role of myeloid derived suppressor cells in promoting ovarian cancer
Rattan R, Sakr S, Quiles R, Morris R, Buekers T, Munkarah A, and Giri S. Role of myeloid derived suppressor cells in promoting ovarian cancer. Cancer Res 2018; 78(13)
Myeloid Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that are increased in tumors and create an immunosuppressive environment by inhibiting the T-cell function. In addition, MDSCs promote angiogenesis, tumor invasion, and metastasis. Increased MDSC accumulation in epithelial ovarian cancer (EOC) has been associated with poor prognosis. Our study investigated whether depletion of MDSCs will influence EOC progression and enhance the therapeutic response of programmed death-1 (PD1) immunotherapy. The intraperitoneal ID8-luciferase syngeneic mouse epithelial ovarian cancer cell model in B6 mice was used for the study ID8 bearing mice exhibited significantly higher levels of MDSCs (CD11bGr1+) (p<0.001) in bone marrow, blood and spleen compared to mice with no tumors control groups, including its sub-populations; granulocytic and monocytic as the tumor progressed. Additionally, the MDSCs isolated from tumor-bearing mice exhibited higher ability to suppress T cell proliferation (p<0.01) and function as reflected by lower IFN-gamma production (p<0.01). Adoptive transfer of tumor educated MDSCs resulted in earlier and aggressive ovarian tumor progression. The adoptively transferred MDSCs (from 45.2 mice) were found to infiltrate in the ovarian tumors of the donor mice (45.1 mice). Once a week treatment of the ID8 tumor bearing mice with the anti-Gr1 specific monoclonal antibody (Ly6G/Ly6C mAb) that targets and depletes MDSCs, resulted in significant retardation in the progression of ovarian cancer in mice as reflected by luciferase based quantification of tumor images (p<0.01), decreased ascites volume (p<0.001) and tumor burden at diaphragm, peritoneal cavity and other organs. Ascitic fluid from tumor bearing mice treated with anti-Gr1 showed decreased MDSC counts associated with an increase in the number of IFN-gamma producing CD4 and CD8 T cells (p<0.01). Also, associated with MDSC depletion and tumor retardation was increase in T-cytotoxic and Thelper cells, and decreased tumor associated macrophages and T-regulatory cells. PD-1 immunotherapy response in ID8 tumors was enhanced in combination with MDSC depletion as seen from decreased tumor burden and restoration of anti-tumor response. Overall, our data suggests that targeting immunosuppression by reducing MDSCs can improve the anti-tumor immune response and aids in containing EOC progression and enhance immunotherapy response. Thus targeting of MDSCs represents a potential therapeutic modality in ovarian cancer and may be considered in combination with other immunotherapies.