Zhang Qingmei, Chan Wing-Lim, Fung Sin-Yee, Pang Li, Ding Tao, Teo Jia Ming Nickolas, Zhou Yuan, Wu Chung Ming Alex, Siu Kam-Leung, Bi Jiacheng, Ling Guang Sheng, Jin Dong-Yan, Man Kwan, Ching Yick Pang
School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China; Department of Surgery, HKU-Shenzhen Hospital and Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China.
Mol Ther. 2025 Jun 4;33(6):2913-2930. doi: 10.1016/j.ymthe.2025.01.043. Epub 2025 Jan 28.
Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered that a hallmark of low TAX1BP2 expression in HCC tumors is T cell exclusion, whereas re-depression of TAX1BP2 in preclinical models restores antitumor immunity and potentiates anti-PD-1 efficacy. Mechanistically, we identified that reconstitution of intratumor TAX1BP2 triggers the type I interferon (IFN-I) response and subsequent facilitation of a subtype of CD27+CD8+ T cell recruitment. Furthermore, we demonstrated that Intratumor TAX1BP2 upregulates STING by inhibiting the hyperactivation of DNMT1, and EZH2 is linked to endogenous LKB1 activity.
中心体异常是人类癌细胞的一个常见特征。我们之前的研究表明，中心体蛋白Tax1结合蛋白2（TAX1BP2）可抑制中心体过度复制，且在肝细胞癌（HCC）中表达不足。在此，我们报告肿瘤内TAX1BP2可促进肿瘤淋巴细胞浸润并增强抗PD-1治疗的疗效。临床上，我们发现HCC肿瘤中TAX1BP2低表达的一个标志是T细胞排除，而在临床前模型中重新抑制TAX1BP2可恢复抗肿瘤免疫力并增强抗PD-1疗效。从机制上讲，我们确定肿瘤内TAX1BP2的重建会触发I型干扰素（IFN-I）反应，并随后促进CD27+CD8+ T细胞亚型的募集。此外，我们证明肿瘤内TAX1BP2通过抑制DNMT1的过度激活而上调STING，且EZH2与内源性LKB1活性相关。
