美国密歇根大学医学院Weiping Zou及其小组的研究发现，泛素连接酶MDM2通过维持STAT5稳定性来调控T细胞介导的抗肿瘤免疫。相关论文于2021年3月25日发表于国际学术期刊《自然-免疫学》杂志。

研究人员发现T细胞MDM2缺陷的小鼠表现出肿瘤进展加速和肿瘤浸润性CD8⁺ T细胞的存活和功能降低。在机制上，MDM2与c-Cbl竞争结合STAT5，从而减弱c-Cbl介导的STAT5降解并增强STAT5在肿瘤浸润性CD8⁺ T细胞中的稳定性。靶向p53 – MDM2与药物APG-115协同作用，可增加T细胞中MDM2的含量，从而稳定STAT5，增强T细胞免疫，并可与癌症免疫疗法协同作用。

令人意外的是，APG-115的这些作用取决于T细胞中的p53和MDM2。在临床上，MDM2丰度与癌症患者T细胞的功能和干扰素-γ信号相关。因此，p53 – MDM2途径可控制T细胞免疫，而针对该途径的靶向治疗可应用于癌症患者，无论其肿瘤细胞内p53的状态如何。

研究人员表示，靶向p53-MDM2途径来重新激活肿瘤细胞内的p53是一种化疗方法。但是，尚不清楚该途径是否也参与CD8⁺ T细胞介导的抗肿瘤免疫。

附：英文原文

Title: The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity

Author: Jiajia Zhou, Ilona Kryczek, Shasha Li, Xiong Li, Angelo Aguilar, Shuang Wei, Sara Grove, Linda Vatan, Jiali Yu, Yijian Yan, Peng Liao, Heng Lin, Jing Li, Gaopeng Li, Wan Du, Weichao Wang, Xueting Lang, Weimin Wang, Shaomeng Wang, Weiping Zou

Issue&Volume: 2021-03-25

Abstract: Targeting the p53–MDM2 pathway to reactivate tumor p53 is a chemotherapeutic approach. However, the involvement of this pathway in CD8+ T cell-mediated antitumor immunity is unknown. Here, we report that mice with MDM2 deficiency in T cells exhibit accelerated tumor progression and a decrease in tumor-infiltrating CD8+ T cell survival and function. Mechanistically, MDM2 competes with c-Cbl for STAT5 binding, reduces c-Cbl-mediated STAT5 degradation and enhances STAT5 stability in tumor-infiltrating CD8+ T cells. Targeting the p53–MDM2 interaction with a pharmacological agent, APG-115, augmented MDM2 in T cells, thereby stabilizing STAT5, boosting T cell immunity and synergizing with cancer immunotherapy. Unexpectedly, these effects of APG-115 were dependent on p53 and MDM2 in T cells. Clinically, MDM2 abundance correlated with T cell function and interferon-γ signature in patients with cancer. Thus, the p53–MDM2 pathway controls T cell immunity, and targeting this pathway may treat patients with cancer regardless of tumor p53 status.

DOI: 10.1038/s41590-021-00888-3

Source: https://www.nature.com/articles/s41590-021-00888-3