PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma

作者：Chuanyuan Wei, Meng-Xuan Zhu, Pengfei Zhang, Xiaoyong Huang, Jinkai Wan, Xiuzhong Yao, Ze-Tao Hu, Xiaoqiang Chai, Rui Peng, Xuan Yang, Chao Gao, Jian Gao, Siwei Wang, Yi-Min Zheng, Zheng Tang, Qiang Gao, Jian Zhou, Jia-Bin Fan, Ai‐Wu Ke, Jia Fan · 发表于：Journal of Hepatology · 年份：2022 · DOI：10.1016/j.jhep.2022.02.019 · 被引用次数：156 · 研究领域：Immune cells in cancer、Ferroptosis and cancer prognosis、Histone Deacetylase Inhibitors Research

BACKGROUND & AIMS: Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed. METHODS: We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64. RESULTS: We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transform...