Abstract 3282: Regorafenib enhance PD-L1 expression via ATM activation and evaluate the therapeutic efficacy of combining PD-L1 antibody on bladder cancer

Abstract

Abstract Bladder cancer is one of the most common cancer in urinary system in Taiwan. According to Ministry of Health and Welfare’s research, bladder cancer plays 15th leading causes of death in Taiwan in 2020. Recently immune checkpoint inhibitor (ICI) therapy show several benefits on preventing T cell exhaustion, accumulating evidences showed ICI therapy still remain some limitation, including unable to regulated immunosuppressor cells and tumor microenvironment (TME) related elements which might lead to ICI therapy dysfunction. Recently, study report that DNA damage may activate the innate immune response and improve ICI efficacy. Thus, regulating DNA damage or illustrate the role of DNA damage related factor may bring the twilight to immunotherapy. To identify the possible combination methods with ICIs, we used MB49 cells and animal model to test the combination property of regorafenib (a multiple receptor tyrosine kinase inhibitor) and 10F.9G2 (a PD-L1 monoclonal antibody). Our research illustrated the mechanism between regorafenib and PD-L1, we proved that regorafenib-induced regulated PD-L1 is associated with ATM activation. TUENL assay showed regorafenib are able to activate ATM by causing DNA break and thus enhance the expression of PD-L1 on tumor surface. This effect could be an important step to open the interaction potential of PD-L1 antibodies and thus enhance its efficacy. Through the interaction analysis of miRNA targeting gene (RNA22), we found that IDO1 mRNA could specifically interact with endogenous miR-124. Here, the propose mechanism in our research is that regorafenib may downregulate IDO1 expression via increasing of endogenous miR-124 expression. In animal model, the combination therapy showed extraordinary therapeutic effect, not only dramatically decreased tumor volume, but also upregulating the positive TME components, such as CD8+T cells and M1 macrophage. Though regorafenib may induce PD-L1 expression, regorafenib still showed several therapeutic benefits, including downregulating immunosuppressive factors, such as IDO1, VEGF, and suppressing the accumulation of regulatory T cells, myeloid-derived suppressor cells and also repolarizing macrophage from M2-to-M1⋯etc. In conclusion, this study points out the combination therapy of regorafenib and anti-PD-L1 has present several benefits to bladder cancer patients and is associated with miR-124/ATM signaling. Citation Format: Kai-Jen Pai, I-Tsang Chiang, Fei-Ting Hsu, Jai-Jen Tsai. Regorafenib enhance PD-L1 expression via ATM activation and evaluate the therapeutic efficacy of combining PD-L1 antibody on bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3282.