小柯机器人

美国斯隆·凯特琳纪念癌症中心Michel Sadelain团队发现，TET2可以防止BATF3诱导的CAR-T细胞扩张。相关论文于2023年2月8日在线发表在《自然》杂志上。

由于T细胞分化和功能状态与不同的表观遗传谱相关，研究人员假设表观遗传编程可能提供一种改善嵌合抗原受体（CAR）-T细胞性能的手段。靶向编码表观遗传调节因子TET2（ten–eleven translocation 2）的基因提供了一个有趣的机会，因为它的缺失可能会增强T细胞记忆，尽管不会引起恶性肿瘤。研究人员发现TET2的破坏增强了白血病和前列腺癌模型中T细胞介导的肿瘤排斥反应。然而，TET2的缺失也会导致不依赖抗原的CAR-T细胞克隆扩增，最终可能导致显著的全身组织浸润。这些克隆性增殖需要双等位基因TET2的破坏和AP-1因子BATF3的表达来驱动MYC依赖的增殖程序。这种增殖状态与不同于典型T细胞记忆和耗竭状态的效应器功能降低有关，并且容易获得继发性体细胞突变，从而建立TET2作为对抗BATF3诱导的CAR-T细胞增殖和随后的基因组不稳定性的守护者。

这些发现阐明了表观遗传编程增强T细胞免疫的潜力，但强调了释放不受控制的增殖反应的风险。

据介绍，细胞工程需要进一步的进展来提高CAR和其他基于T细胞治疗的效率。

附：英文原文

Title: TET2 guards against unchecked BATF3-induced CAR T cell expansion

Author: Jain, Nayan, Zhao, Zeguo, Feucht, Judith, Koche, Richard, Iyer, Archana, Dobrin, Anton, Mansilla-Soto, Jorge, Yang, Julie, Zhan, Yingqian, Lopez, Michael, Gunset, Gertrude, Sadelain, Michel

Issue&Volume: 2023-02-08

Abstract: Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies1,2,3,4,5. As T cell differentiation and functional states are associated with distinct epigenetic profiles6,7, we hypothesized that epigenetic programming may provide a means to improve CAR T cell performance. Targeting the gene that encodes the epigenetic regulator ten–eleven translocation 2 (TET2)8 presents an interesting opportunity as its loss may enhance T cell memory9,10, albeit not cause malignancy9,11,12. Here we show that disruption of TET2 enhances T cell-mediated tumour rejection in leukaemia and prostate cancer models. However, loss of TET2 also enables antigen-independent CAR T cell clonal expansions that may eventually result in prominent systemic tissue infiltration. These clonal proliferations require biallelic TET2 disruption and sustained expression of the AP-1 factor BATF3 to drive a MYC-dependent proliferative program. This proliferative state is associated with reduced effector function that differs from both canonical T cell memory13,14 and exhaustion15,16 states, and is prone to the acquisition of secondary somatic mutations, establishing TET2 as a guardian against BATF3-induced CAR T cell proliferation and ensuing genomic instability. Our findings illustrate the potential of epigenetic programming to enhance T cell immunity but highlight the risk of unleashing unchecked proliferative responses.

DOI: 10.1038/s41586-022-05692-z

Source: https://www.nature.com/articles/s41586-022-05692-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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