新加坡基因组研究所Qiang Yu研究团队发现，靶向P4HA1促进CD8⁺ T细胞前体扩增并推动免疫记忆和系统性抗肿瘤免疫。2024年12月26日，《癌细胞》杂志在线发表了这项成果。

研究人员发现编码脯氨酰4-羟化酶1（P4HA1）的基因，是CD8⁺ T细胞分化的关键调节因子，在肿瘤引流淋巴结（TDLN）和缺氧的肿瘤微环境中显著上调。

P4HA1积累在线粒体中，通过异常的α-酮戊二酸和琥珀酸代谢，破坏三羧酸循环，促进线粒体功能失调和细胞衰竭，并同时抑制前体细胞扩增。靶向P4HA1可增强采用性和内源性TCF1⁺ CD8⁺ T前体的扩增，同时减轻肿瘤、TDLN和血液中的衰竭发展，促使显著且持久的系统性抗癌免疫反应。

研究人员提出，癌症中CD8⁺ T细胞对P4HA1的诱导会引发免疫逃逸程序，这提供了一种面向T细胞的靶点，可用于实体肿瘤的系统免疫治疗。

据介绍，成功的免疫治疗依赖于肿瘤内部和全身免疫，但对于大多数癌症患者来说，这一目标尚未实现。

附：英文原文

Title: Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity

Author: Shijun Ma, Li-Teng Ong, Zemin Jiang, Wee Chyan Lee, Puay Leng Lee, Mubaraka Yusuf, Henrik J. Ditzel, Yulan Wang, Qingfeng Chen, Wenyu Wang, Xiaojian Wu, Ern Yu Tan, Qiang Yu

Issue&Volume: 2024-12-26

Abstract: Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with cancer. Here, we identify P4HA1, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8+ T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1+ CD8+ T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8+ T cells in cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors.

DOI: 10.1016/j.ccell.2024.12.001

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00476-8