ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells
ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells
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ZFP91 扰乱肿瘤浸润 T 细胞的代谢适应性和抗肿瘤活性
DOI：
10.1172/jci144318
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发表时间：
2021
影响因子：
15.9
通讯作者：
Zou Qiang
中科院分区：
文献类型：
--
作者：
Wang Feixiang;Zhang Yuerong;Yu Xiaoyan;Teng Xiao-Lu;Ding Rui;Hu Zhilin;Wang Aiting;Wang Zhengting;Ye Youqiong;Zou Qiang
适当的代谢活动促进T细胞扩增和抗肿瘤功能;然而，肿瘤微环境（TME）中T细胞代谢程序和功能破坏的潜在机制仍然难以捉摸。在这里，我们展示了一种锌指蛋白91调控（ZFP 91调控）机制，该机制破坏了肿瘤浸润T细胞的代谢途径和抗肿瘤活性。单细胞RNA-Seq显示，在结直肠癌患者的组织样本中，T细胞增殖和活化的损伤与ZFP 91相关。小鼠T细胞特异性缺失Zfp 91导致T细胞增殖增强和增强T细胞抗肿瘤功能。ZFP 91的缺失增加了哺乳动物雷帕霉素复合物1靶蛋白（mTORC 1）的活性，以驱动T细胞糖酵解。从机制上讲，T细胞抗原受体依赖性（TCR依赖性）ZFP 91胞质易位促进蛋白磷酸酶2A（PP 2A）复合物组装，从而限制mTORC 1介导的代谢重编程。我们的研究结果表明，ZFP 91扰乱了TME中的T细胞代谢和功能状态，并表明靶向ZFP 91可以提高癌症免疫治疗的疗效。
Proper metabolic activities facilitate T cell expansion and antitumor function; however, the mechanisms underlying disruption of the T cell metabolic program and function in the tumor microenvironment (TME) remain elusive. Here, we show a zinc finger protein 91–governed (ZFP91-governed) mechanism that disrupts the metabolic pathway and antitumor activity of tumor-infiltrating T cells. Single-cell RNA-Seq revealed that impairments in T cell proliferation and activation correlated with ZFP91 in tissue samples from patients with colorectal cancer. T cell–specific deletion ofZfp91in mice led to enhanced T cell proliferation and potentiated T cell antitumor function. Loss of ZFP91 increased mammalian target of rapamycin complex 1 (mTORC1) activity to drive T cell glycolysis. Mechanistically, T cell antigen receptor–dependent (TCR-dependent) ZFP91 cytosolic translocation promoted protein phosphatase 2A (PP2A) complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming. Our results demonstrate that ZFP91 perturbs T cell metabolic and functional states in the TME and suggest that targeting ZFP91 may improve the efficacy of cancer immunotherapy.