Abstract 2751: Regorafenib attenuates IFN-γ-induced PD-L1 expression and enhances antitumor immunity

Abstract

Abstract Immune checkpoint blocked therapy (ICB) targeting the PD-1/PD-L1 axis induce durable tumor regressions in a sizeable minority of cancer patients. To enhance the efficacy of existing immunotherapies, we implemented a screen of kinase inhibitors capable of increasing the activity of T cells suppressed by PD-L1. Here, we identified regorafenib, which was approved to treat patients with advanced gastrointestinal stromal tumors and metastatic colorectal cancer, as a potent agent significantly attenuating IFN-γ-induced PD-L1 expression without affecting MHC-I expression, contributing to enhanced anti-tumor effects with ICB in vitro and in vivo, due in part to inhibit JAK1/2-STAT1 signaling and the activation of ERK by suppressing the tyrosine kinase receptor RET-Src axis. Additionally, our analysis of GEO database and TCGA database revealed that RET and Src co-high expression was an independent unfavorable prognosis factor in both melanoma patients with or without ICB via inhibiting anti-tumor immune response. Further, gene set enrichment analysis (GSEA) demonstrated, compared to RET and Src co-high expression group, anti-tumor immune response related gene signatures as prominent modules in other group. Collectively, our data unveiled a new mechanism of reducing IFN-γ-induced PD-L1 expression and provided a rationale to explore a new combination of immunotherapies and regorafenib in melanoma treatment. Citation Format: Xiao-Feng Zhu. Regorafenib attenuates IFN-γ-induced PD-L1 expression and enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2751.