Abstract B087: Targeting myeloid derived suppressor cell migration decreases tumor progression in a murine model of ovarian cancer

Abstract

Abstract Introduction: High grade serous ovarian, fallopian tube and primary peritoneal carcinoma (HGSC) has an immunosuppressive and tumor promoting immune microenvironment. In this study, we have targeted the migration of myeloid derived suppressor cells (MDSC) through chemical inhibition of the CXCR2 chemotactic receptor to reverse the tumor-induced immunosuppression.Methods: ID8 cells with a p53 mutation (ID8-P53null) were used as a murine model of HGSC. ID8-p53null cells were injected intraperitoneally into immune intact C57/Bl6 mice, with 10 mice per group. After 7 days, mice were treated with cisplatin (cis, 1mg/kg, i.p., weekly), a CXCR2 inhibitor (CXCR2i, 4mg/kg, i.p., daily) or a combination of the 2 treatments. Necropsy was performed on day 29. The tumors were weighed, and the number of metastatic sites was quantified. The spleen and the tumor were resected, digested and flow cytometry was performed to evaluate the effects of treatment on the tumor immune microenvironment (TIME) as well as any systemic changes (evaluated by immune cells in the spleen). Granulocytic MDSC (G-MDSC) and monocytic MDSCs (M-MDSC) were defined as CD11b+Ly6G+,Ly6Clo and CD11b+Ly6G−Ly6Chi, respectively. One-way ANOVA with Tukey multiple comparisons was used for statistics with p<0.05 as the cut off for significance. Results: Tumor weights were significantly less in cis treated vs control mice (0.064g vs 0.220g, p <0.001) and CXCR2i treated vs control mice (0.171g vs 0.220g, p=.003). There was no additive effect of the CXCR2i to the cis treatment (cis 0.064g vs cis + CXCR2i 0.049g, p=0.62). The number of metastatic sites as a measurement of dissemination also decreased with cis or CXCR2i (number of sites: control: 47 vs cis: 12.7 vs CXCR2i: 32.5 vs cis + CXCR2i: 10.2). When the TIME was evaluated by flow cytometry, there were no significant differences in the immune populations including T-cells, NK cells, myeloid cells, and macrophages. However, there was a trend for cis to increase both the G-MDSC and M-MDSC populations and this effect was inhibited with the combination treatment of cis and CXCR2i. For the G-MDSC population control: 0.6% vs cis: 0.9% vs cis+CXCR2i: 0.5% and M-MDSC population control 3.4% vs cis: 6.8% vs cis+CXCR2i: 2.6%. Conclusion: CXCR2 is a chemotactic receptor present on MDSCs. We targeted this receptor to decrease the migration and infiltration of MDSCs into the ovarian cancer TIME. The CXCR2i decreased tumor progression in the ID8-p53null model of ovarian cancer. The TIME was evaluated by flow cytometry, and there was a trend for cis to increase the suppressive MDSC populations and this increase was inhibited by the CXCR2i. These exciting data suggest that traditional chemotherapy may lead to a more immunosuppressive TIME, which could have implications for future recurrence and treatment. Blocking the migration of immunosuppressive cells into the TIME may have a long-term impact on survival in HGSC. Survival studies in this murine model of HGSC are currently underway. Citation Format: Nicole Marjon, Railey Mikeska, Elizabeth R. Woodruff, Ritsuko Iwanaga, Tomomi Yamamoto, Benjamin G. Bitler. Targeting myeloid derived suppressor cell migration decreases tumor progression in a murine model of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B087.