美国宾夕法尼亚大学Christoph T. Ellebrecht和美国哥伦比亚大学Aimee S. Payne共同合作，近期取得重要工作进展。他们研究提出，可以通过不对称细胞分裂诱导CD8 CAR T细胞的命运。相关研究成果2024年8月28日在线发表于《自然》杂志上。

据介绍，早期扩增和长期持续可以预测嵌合抗原受体T细胞（CART）的疗效，但调控效应细胞与记忆CART分化的机制以及不对称细胞分裂是否诱导人类CART的不同命运尚不清楚。

研究人员表明靶诱导的邻近标记能够分离第一分裂近端子代和远端子代CD8 CART，它们不对称地分布其表面蛋白质组和转录组，导致不同的命运。靶向结合的CAR保留在近端子细胞上，这些子细胞继承了类似于活化的未分裂CART的表面蛋白质组，而内源性T细胞受体和CD8富集在远端子细胞上。远端子细胞的表面蛋白质组成类似于静息CART，分别与糖酵解和氧化代谢相关。

尽管存在记忆前体表型和体内寿命，但远端子细胞表现出与近端子细胞相似的瞬时强效细胞溶解活性，揭示了远端子细胞中注定会成为记忆CART的效应器样状态。预先存在的转录物的分割和RNA速度的变化都会导致命运决定因素的不对称，从而导致截然相反的转录轨迹。与幼稚、记忆或效应器表面免疫表型无关，近端子细胞CART使用已知支持增殖和效应器功能的核心转录因子集。相反，IKZF1破坏后，远端子细胞CART的长期体内持久性和功能降低，证明了远端子细胞中富集的转录因子抑制分化并促进寿命。

总之，这一研究将不对称细胞分裂确立为理解CART分化机制和改善治疗结果的框架。

附：英文原文

Title: Fate induction in CD8 CAR T cells through asymmetric cell division

Author: Lee, Casey S., Chen, Sisi, Berry, Corbett T., Kelly, Andre R., Herman, Patrick J., Oh, Sangwook, OConnor, Roddy S., Payne, Aimee S., Ellebrecht, Christoph T.

Issue&Volume: 2024-08-28

Abstract: Early expansion and long-term persistence predict efficacy of chimeric antigen receptor T cells (CARTs)1,2,3,4,5,6,7, but mechanisms governing effector versus memory CART differentiation and whether asymmetric cell division induces differential fates in human CARTs remain unclear. Here we show that target-induced proximity labelling enables isolation of first-division proximal-daughter and distal-daughter CD8 CARTs that asymmetrically distribute their surface proteome and transcriptome, resulting in divergent fates. Target-engaged CARs remain on proximal daughters, which inherit a surface proteome resembling activated-undivided CARTs, whereas the endogenous T cell receptor and CD8 enrich on distal daughters, whose surface proteome resembles resting CARTs, correlating with glycolytic and oxidative metabolism, respectively. Despite memory-precursor phenotype and in vivo longevity, distal daughters demonstrate transient potent cytolytic activity similar to proximal daughters, uncovering an effector-like state in distal daughters destined to become memory CARTs. Both partitioning of pre-existing transcripts and changes in RNA velocity contribute to asymmetry of fate-determining factors, resulting in diametrically opposed transcriptional trajectories. Independent of naive, memory or effector surface immunophenotype, proximal-daughter CARTs use core sets of transcription factors known to support proliferation and effector function. Conversely, transcription factors enriched in distal daughters restrain differentiation and promote longevity, evidenced by diminished long-term in vivo persistence and function of distal-daughter CARTs after IKZF1 disruption. These studies establish asymmetric cell division as a framework for understanding mechanisms of CART differentiation and improving therapeutic outcomes.

DOI: 10.1038/s41586-024-07862-7

Source: https://www.nature.com/articles/s41586-024-07862-7