CD8 + T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting TET2 in CAR T cells provides therapeutic benefit; however, TET2’s role in exhausted T cell (T EX ) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell–like T EX progenitors toward terminally differentiated and effector (T EFF )–like T EX . TET2 also enforced a terminally differentiated state in the early bifurcation between T EFF and T EX , indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable TET2- targeted CAR T cells by disrupting TET2 via knock-in of a safety switch alongside CAR knock-in at the TRAC locus. TET2 -targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in T EX differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.

中文翻译：

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TET2 调节耗竭 CD8 + T 细胞分化的早期和晚期转变并限制 CAR T 细胞功能


CD8 + T 细胞耗竭阻碍了癌症和慢性感染的控制，并限制了嵌合抗原受体 （CAR） T 细胞的疗效。在 CAR T 细胞中靶向 TET2 可提供治疗益处;然而，TET2 在耗竭 T 细胞 （T EX） 发育中的作用尚不清楚。在慢性淋巴细胞性脉络丛脑膜炎病毒 （LCMV） 感染中，TET2 驱动从干细胞样 T EX 祖细胞向终末分化和效应器 （T EFF） 样 T EX 的转化。TET2 还在 T EFF 和 T EX 之间的早期分叉中强制执行了终末分化状态，表明 TET2 在效应子生物学的获得中具有广泛的作用。为了开发 TET2 的治疗潜力，我们通过在 TRAC 基因座敲入安全开关和 CAR 敲入来破坏 TET2，从而开发了临床可操作的 TET2 靶向 CAR T 细胞。TET2 靶向的 CAR T 细胞在体外表现出抑制的终末耗竭，并在体内表现出增强的抗肿瘤反应。因此，TET2 调节 T EX 分化的命运转换，并且可以在 CAR T 细胞中以安全机制为靶点，以改善肿瘤控制。