Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma

作者：Zhuo Yu, Yuyao Li, Yue Li, Jinghao Zhang, Man Li, Longshan Ji, Yifei Tang, Yangqing Zheng, Jianguo Sheng, Qiucheng Han, Li Fu, Jianfeng Guo, Lingtai Wang, Xuehua Sun, Yueqiu Gao, Hai Feng · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2021-004297 · 被引用次数：124 · 研究领域：Immune cells in cancer、Immunotherapy and Immune Responses、Phagocytosis and Immune Regulation

BACKGROUND: Immunotherapy for hepatocellular carcinoma (HCC) exhibits limited clinical efficacy due to immunosuppressive tumor microenvironment (TME). Tumor-infiltrating macrophages (TIMs) account for the major component in the TME, and the dominance of M2 phenotype over M1 phenotype in the TIMs plays the pivotal role in sustaining the immunosuppressive character. We thus investigate the effect of bufalin on promoting TIMs polarization toward M1 phenotype to improve HCC immunotherapy. METHODS: The impact of bufalin on evoking antitumor immune response was evaluated in the immunocompetent mouse HCC model. The expression profiling of macrophage-associated genes, surface markers and cytokines on bufalin treatment in vitro and in vivo were detected using flow cytometry, immunofluorescence, western blot analysis, ELISA and RT-qPCR. Cell signaling involved in M1 macrophage polarization was identified via the analysis of gene sequencing, and bufalin-governed target was explored by immunoprecipitation, western blot analysis and gain-and-loss of antitumor immune response. The combination of bufalin and antiprogrammed cell death protein 1 (anti-PD-1) antibody was also assessed in orthotopic HCC mouse model. RESULTS: In this study, we showed that bufalin can function as an antitumor immune modulator that governs the polarization of TIMs from tumor-promoting M2 toward tumor-inhibitory M1, which induces HCC suppression through the activation of effector T cell immune response. Mechanistic...