Depletion of immunosuppressive myeloid-derived suppressor cells impedes ovarian cancer growth

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Conference Proceeding

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Gynecol Oncol


Objective: 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 aim was to investigate whether depletion of MDSCs influences EOC progression. Method: The intraperitoneal ID8 syngeneic mouse epithelial ovarian cancer cell model in B6 mice was used for the study. The ID8 tumorbearing mice were treated once a week with either the anti-Gr1 specific antibody (Ab) that targets and depletes MDSCs or its isotype IgG2b Ab as control (100 μg/dose/mouse). Mice were sacrificed at day 60 for tumor burden evaluation. Quantification of various immune cells in blood, spleen, bone marrow, and ascites was performed by fluorescence-activated cell sorter (FACS) using specific cell surface markers and by immunohistochemistry (IHC). Cytokine levels were measured by ELISA. Results: ID8 tumor-bearing mice exhibited significantly higher levels of granulocytic (CD11b+Gr1high) and monocytic (CD11b+Gr1low) MDSCs (P b 0.001) in bone marrow, blood, and spleen compared to control mice with no tumors. When compared to MDSCs retrieved from the spleens of control nontumor-bearing mice, MDSCs isolated from tumor-bearing mice exhibited higher ability to suppress T cell proliferation (P b 0.01) and function as reflected by lower IFNgamma production (P b 0.01). Depletion of MDSCs using anti-Gr1 antibody significantly retarded the progression of ovarian cancer in mice as reflected by decreased ascites volume (P b 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 b 0.01). Conclusion: Our data suggest that reducing MDSCs can improve the antitumor immune response and AIDS in containing EOC progression. Thus targeting of MDSCs represents a potential therapeutic modality in ovarian cancer and may be considered in combination with other immunotherapies including T cell-based therapies.



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