肿瘤细胞治疗研究
英文原题：CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency.
通过靶向等位基因重编程（ROADSTAR）对激活依赖性信号进行合理优化，我们的这一方法说明了针对 CAR 设计特异性微调内在 T 细胞信号的重要性，并展示了碱基编辑用于下一代细胞治疗的潜力。
嵌合抗原受体（CAR）疗法的功能性T细胞持久性不足，妨碍治疗成功。本研究针对T细胞功能、代谢及命运的关键调节因子PIK3CD，开展适配CAR的碱基编辑筛选。研究发现，特定点突变可分别有利地调节4-1BBζ和28ζ CAR-T细胞特征。对磷脂酰肌醇-3-激酶δ（PI3Kδ）信号活性产生不同影响的点突变，在不同CAR背景下各具优势：激活PI3Kδ的E81K突变可增强4-1BBζ CAR-T细胞增殖、代谢适应性和效应功能，促进长期功能持久性并提高体内治疗效果；相反，减弱PI3Kδ的L32P突变可改善28ζ CAR-T细胞的记忆形成和功能。综上，研究提出通过靶向等位基因重编程对激活依赖性信号进行理性优化的方法（ROADSTAR），说明根据CAR设计精细调节T细胞内源信号十分重要，并展示了碱基编辑用于下一代细胞疗法的潜力。
Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3K ) signaling activity were advantageous in distinct CAR contexts: The PI3K -activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3K -attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies.
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