CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
清除 CAR-T 细胞中的 BATF 通过诱导抗耗竭及中央记忆细胞形成增强抗肿瘤活性
英文原题：Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells.
查看英文原题
Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells.
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中文摘要
嵌合抗原受体（CAR）T细胞疗法对实体瘤的疗效有限，其中一个主要挑战是T细胞耗竭。为应对这一挑战，我们利用功能低下的CAR-T 细胞模型进行了候选基因筛选，发现敲除碱性亮氨酸拉链ATF样转录因子（BATF）可改善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缺失使T细胞具有更强的抗耗竭能力和更优的肿瘤清除疗效。在机制上，我们发现BATF在人CAR-T 细胞中结合并上调一部分耗竭相关基因。BATF调控参与效应T细胞和记忆T细胞发育的基因表达，敲除BATF使细胞群体向更偏向中央记忆亚群转变。我们证明BATF是限制CAR-T 细胞功能的关键因子，其缺失增强了CAR-T 细胞对实体瘤的抗肿瘤活性。
展开英文摘要原文
Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors, and one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model and found that depletion of basic leucine zipper ATF-like transcription factor (BATF) improved the antitumor performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, loss of BATF endows T cells with improved resistance to exhaustion and superior tumor eradication efficacy.
Mechanistically, we found that BATF binds to and up-regulates a subset of exhaustion-related genes in human CAR-T cells. BATF regulates the expression of genes involved in development of effector and memory T cells, and knocking out BATF shifts the population toward a more central memory subset.
We demonstrate that BATF is a key factor limiting CAR-T cell function and that its depletion enhances the antitumor activity of CAR-T cells against solid tumors.
论文信息
- 作者
- Zhang X、Zhang C、Qiao M、Cheng C、Tang N、Lu S、Sun W、Xu B
- 第一作者单位
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.China
- 通讯作者单位
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: wanghaoyi@ioz.ac.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Cancer cell2022 Nov 14
- 原文标识
- PubMed 36240777 · DOI 10.1016/j.ccell.2022.09.013