Myeloid-derived suppressor cell depletion augments antitumor activity in ovarian cancer

Document Type

Conference Proceeding

Publication Date

2018

Publication Title

Clin Cancer Res

Abstract

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 syngeneic mouse epithelial ovarian cancer cell model in B6 mice was used for the study. The ID8 tumor-bearing mice were treated once a week with either the anti-Gr1 specific monoclonal antibody (Ly6G/Ly6C mAb) that targets and depletes MDSCs, or its isotype IgG2b mAb as control (100μg/dose/mouse). Mice were sacrificed at day 60 for tumor burden evaluation. Quantification of various immune cells and their effector cytokines in blood, spleen, bone marrow, ascites, and tumor were performed by fluorescence-activated cell sorter (FACS) using specific cell surface and intracellular markers, ELISA, and by immunohistochemistry (IHC). The preclinical trial of anti-GR1 and anti-PD1 Ab combination was also carried out. 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 subpopulations, granulocytic (CD11b+Gr1high) and monocytic (CD11b+Gr1low). When compared to MDSCs retrieved from the spleens of control non-tumor bearing mice, 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). Depletion of MDSCs using anti-Gr1 antibody significantly retarded the progression of ovarian cancer in mice as reflected by decreased ascites volume (p<0.001) and tumor burden at the 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 an increase in T-cytotoxic and T-helper cells, and decreased tumor-associated macrophages and T-regulatory cells. PD-1 immunotherapy response in ID8 tumors was enhanced in combination with MDSC depletion. Overall, our data suggest that reducing MDSCs can improve the antitumor immune response and aids in containing EOC progression and enhancing immunotherapy response. Thus, targeting of MDSCs represents a potential therapeutic modality in ovarian cancer and may be considered in combination with other immunotherapies.

Volume

24

Issue

15

First Page

98

Last Page

99

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