小柯机器人

中国科学院动物研究所王皓毅团队发现，嵌合抗原受体(CAR) T细胞中基本亮氨酸拉链ATF样转录因子(BATF)的消耗，通过诱导抗衰竭和中枢记忆细胞的形成增强抗肿瘤活性。相关论文于2022年10月13日发表在《癌细胞》杂志上。

为了应对T细胞衰竭的挑战，他们使用功能低下的CAR-T细胞模型进行了候选基因筛选，发现BATF的缺失提高了CAR-T细胞的抗肿瘤性能。在不同类型的CAR-T细胞和小鼠OT-1细胞中，BATF的丢失使T细胞具有更好的抗衰竭能力和更好的肿瘤根除效果。

从机制上讲，他们发现BATF结合并上调了人类CAR-T细胞中疲劳相关基因的亚群。BATF调节与效应T细胞和记忆T细胞发育有关的基因的表达，而敲除BATF将主群转移到更集中的记忆亚群。他们证明BATF是限制CAR-T细胞功能的一个关键因素，它的缺失增强了CAR-T细胞对实体肿瘤的抗肿瘤活性。

据介绍，CAR-T细胞治疗对实体瘤的疗效有限，一个主要挑战是T细胞衰竭。

附：英文原文

Title: Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells

Author: Xingying Zhang, Chenze Zhang, Miaomiao Qiao, Chen Cheng, Na Tang, Shan Lu, Wen Sun, Beilei Xu, Yuanwei Cao, Xiaofei Wei, Yao Wang, Weidong Han, Haoyi Wang

Issue&Volume: 2022-10-13

Abstract: Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solidtumors, and one major challenge is T cell exhaustion. To address this challenge, weperformed a candidate gene screen using a hypofunction CAR-T cell model and foundthat depletion of basic leucine zipper ATF-like transcription factor (BATF) improvedthe antitumor performance of CAR-T cells. In different types of CAR-T cells and mouseOT-1 cells, loss of BATF endows T cells with improved resistance to exhaustion andsuperior tumor eradication efficacy. Mechanistically, we found that BATF binds toand up-regulates a subset of exhaustion-related genes in human CAR-T cells. BATF regulatesthe expression of genes involved in development of effector and memory T cells, andknocking out BATF shifts the population toward a more central memory subset. We demonstrate that BATFis a key factor limiting CAR-T cell function and that its depletion enhances the antitumoractivity of CAR-T cells against solid tumors.

DOI: 10.1016/j.ccell.2022.09.013

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00442-1

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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