The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 1]

Despite remarkable achievements, majority of hepatocellular carcinoma (HCC) patients fail to respond to anti-PD1 therapy. Here, we showed that ZFP64 was frequently upregulated in HCC tissues of anti-PD1 resistance patients. Elevated ZFP64 levels triggered tumor progression and induced an immunosuppressive microenvironment. Mechanistically, ZFP64 transcriptionally activated colony-stimulating factor 1 (CSF1) by directly binding to its promoter, and secreted CSF1 driving the shift of macrophages into an alternatively activated phenotype. Importantly, the PKCα was revealed to phosphorylate ZFP64 at S226, resulting in its nuclear translocation to transcribe the CSF1 gene. Particularly, we proposed firstly that the PKCα/ZFP64/CSF1 axis was a critical pathway in fostering immune evasion and anti-PD1 tolerance and inhibiting this axis with lenvatinib or Gö6976 surmounted the anti-PD1 resistance in HCC. Our study indicates that the ZFP64 is an emerging indicator in predicting anti-PD1 efficacy, and reveals the PKCα/ZFP64/CSF1 axis is a suitable target for anti-PD1 combination therapy in HCC. mRNA profiles of tumor tissues in PD and PR HCC patients

尽管肝细胞癌（hepatocellular carcinoma, HCC）治疗领域已取得诸多显著进展，但绝大多数患者仍无法从抗PD1治疗中获益。本研究发现，ZFP64在抗PD1治疗耐药的肝细胞癌患者癌组织中呈高频上调表达。ZFP64表达升高可促进肿瘤进展，并诱导免疫抑制性肿瘤微环境形成。机制层面，ZFP64可通过直接结合集落刺激因子1（colony-stimulating factor 1, CSF1）的启动子区域对其进行转录激活，其分泌的CSF1可驱动巨噬细胞向交替激活表型极化。尤为重要的是，本研究证实蛋白激酶Cα（PKCα）可在丝氨酸226（S226）位点对ZFP64进行磷酸化修饰，促使其发生核转位并启动CSF1基因的转录。尤为特别的是，本研究首次提出PKCα/ZFP64/CSF1信号轴是介导肝细胞癌免疫逃逸与抗PD1治疗耐受的关键通路，通过仑伐替尼（lenvatinib）或Gö6976抑制该信号轴，可逆转肝细胞癌的抗PD1治疗耐药性。本研究表明，ZFP64可作为预测抗PD1治疗疗效的新型生物标志物，并证实PKCα/ZFP64/CSF1信号轴是肝细胞癌抗PD1联合治疗的潜在靶点。本数据集包含抗PD1治疗后疾病进展（PD）与部分缓解（PR）的肝细胞癌患者的癌组织mRNA表达谱。