Abstract 954: Adverse immunomodulatory effects of chemotherapy on myeloid-derived suppressor cell compromise immune-checkpoint blockade efficacy

Abstract

Abstract Introduction: Intrinsic immunologic composition in liver tumor microenvironment (TME) may play a role in the heterogenous response towards immune-checkpoint blockade in hepatocellular carcinoma (HCC). In some cancers, it has been shown that cytotoxic chemotherapy is synergistic with checkpoint inhibitors. In this study, we evaluated the efficacy and immunomodulation of 5-FU and anti-PD-L1 in orthotopic liver cancer mouse model. Method: The orthotopic mouse model was established with the murine HCC cell line RIL-175 through intrahepatic injection. The tumor-bearing mice was then treated with 5-FU (i.p.) 3 times per week at 20mg/kg. Anti-PD-L1(10mg/kg) was delivered (i.p.) every 5 days. Tumor growth was reflected by the luciferase intensity via in vivo imaging. Upon sacrifice, the tumor tissue, liver, spleen and blood sample were harvested, followed by subsequent immune profiling analysis using flow cytometry. Results: Based on the tumor growth rate and endpoint tumor weight, anti-PD-L1 monotherapy induced a significant tumor reduction whereas 5-FU, either alone or combined with anti-PD-L1, did not have therapeutic effect as compared to vehicle control. Proportions of immunosurveillance cells including natural killer (NK) cells, CD8+ T cells and CD4+ T cells were drastically increased in the tumor site after anti-PD-L1 single treatment, but reduced in 5-FU-treated tumor. To depict the underlying regulation by chemotherapy, immunosuppressive components were also examined. Accumulation in myeloid cells, particularly CD11b+Gr-1+Ly6G+Ly6Cint polymorphonuclear myeloid-derived suppressor cells (P-MDSCs) were found to be a contributing factor to lymphocytes depletion when treated with 5-FU, hence counteracting the anti-tumor activity by PD-L1 blockade. Conclusion: In summary, our data indicate that chemotherapeutics may impose immunosuppressive modulation in HCC TME and latently alter the therapeutic outcome against immune-checkpoint blockade. This study suggests that combination of chemotherapy with checkpoint inhibitors may not be a feasible approach for HCC. Acknowledgement: The study is supported by the Terry Fox Foundation. Key Words: Tumor microenvironment (TME), Hepatocellular carcinoma, Chemotherapy, myeloid-derived suppressor cell (MDSC), anti-PD-L1, immunotherapy Citation Format: Tsz Tung Kwong, Chi Hang Wong, Jing Ying Zhou, Alfred Sze Lok Cheng, Anthony Wing Hung Chan, Stephen Lam Chan. Adverse immunomodulatory effects of chemotherapy on myeloid-derived suppressor cell compromise immune-checkpoint blockade efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 954.