Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, China.
J Immunother Cancer. 2024 Nov 5;12(11):e010422. doi: 10.1136/jitc-2024-010422.
Immune checkpoint inhibitors (ICIs) are therapeutically effective for hepatocellular carcinoma (HCC) but are individually selective. This study examined the role of specific common fragile sites (CFSs) related gene in HCC immunotherapy.
We analyzed HCC tissues using next-generation sequencing and flow cytometry via time-of-flight technology. A humanized orthotopic HCC mouse model, an in vitro co-culture system, untargeted metabolomics and a DNA pulldown assay were used to examine the function and mechanism of WWOX in the tumor immune response.
WWOX was the most upregulated CFS-related gene in HCC patients responsive to ICIs. WWOX deficiency renders HCC resistant to PD-1 treatment in humanized orthotopic HCC mouse model. Macrophage infiltration is increased and CD8 T-cell subset infiltration is decreased in WWOX-deficient HCC patients. HCC-derived oleic acid (OA) promotes macrophage conversion to an immunosuppressive phenotype. Mechanistically, WWOX deficiency promoted OA synthesis primarily via competitive binding of NME2 with KAT1, which promoted acetylation of NME2 at site 31 and inhibited NME2 binding to the SCD5 promoter region. Pharmacological blockade of SCD5 enhanced the antitumor effects of anti-PD-1 therapy.
WWOX is a key factor for immune escape in HCC patients, which suggests its use as a biomarker for stratified treatment with ICIs in clinical HCC patients.
免疫检查点抑制剂（ICIs）在治疗肝细胞癌（HCC）方面具有疗效，但个体选择性强。本研究探讨了特定常见脆弱位点（CFSs）相关基因在 HCC 免疫治疗中的作用。
我们通过飞行时间技术的下一代测序和流式细胞术分析 HCC 组织。使用人源化原位 HCC 小鼠模型、体外共培养系统、非靶向代谢组学和 DNA 下拉测定来研究 WW0X 在肿瘤免疫反应中的功能和机制。
WW0X 是对 ICI 有反应的 HCC 患者中上调最明显的 CFS 相关基因。WW0X 缺失使 HCC 对 PD-1 治疗产生耐药性，在人源化原位 HCC 小鼠模型中。WW0X 缺陷 HCC 患者的巨噬细胞浸润增加，CD8 T 细胞亚群浸润减少。HCC 衍生的油酸（OA）促进巨噬细胞向免疫抑制表型转化。在机制上，WW0X 缺失通过 NME2 与 KAT1 的竞争结合促进 OA 合成，这促进了 NME2 在第 31 位的乙酰化，并抑制了 NME2 与 SCD5 启动子区域的结合。SCD5 的药物阻断增强了抗 PD-1 治疗的抗肿瘤作用。
WW0X 是 HCC 患者免疫逃逸的关键因素，提示其可作为临床 HCC 患者接受 ICI 分层治疗的生物标志物。
