美国科罗拉多大学Terry J. Fry研究组发现，抗原经验历史引导CD8⁺ CAR T细胞在抗白血病反应中的不同功能状态。相关论文于2025年1月2日在线发表于国际学术期刊《自然—免疫学》。

研究人员探讨了特定抗原经验对后续CD8⁺ 嵌合抗原受体（CAR）T细胞活性的影响。先前的抗原接触导致在低靶抗原密度的白血病中，效应功能优于其他状态，但以减少增殖能力和在限制性CAR剂量下对功能丧失的敏感性为代价。

通过分析来源于初始细胞和记忆细胞的CAR T细胞的时间性转录组学和表观遗传学特征，研究人员识别出RUNX家族转录因子作为潜在靶点，以增强来源于初始细胞的CD8⁺ CAR T细胞的功能。

RUNX2的过表达增强了小鼠CAR T细胞的抗肿瘤效能，这依赖于细胞的先前状态，并提高了人类CAR T细胞的功能。这些数据表明，CAR T细胞的抗原经验决定了其功能特征，并能够通过转录因子介导的功能增强来改善其效能。

研究人员表示，尽管CAR T细胞对B谱系恶性肿瘤有效，但CAR治疗后复发常见，且在其他肿瘤中的疗效有限。这些挑战可以通过合理的操作来控制CAR T细胞的功能。

附：英文原文

Title: Antigen experience history directs distinct functional states of CD8+ CAR T cells during the antileukemia response

Author: DeGolier, Kole R., Danis, Etienne, DAntonio, Marc, Cimons, Jennifer, Yarnell, Michael, Kedl, Ross M., Kohler, M. Eric, Scott-Browne, James P., Fry, Terry J.

Issue&Volume: 2025-01-02

Abstract: Although chimeric antigen receptor (CAR) T cells are effective against B-lineage malignancies, post-CAR relapse is common, and efficacy in other tumors is limited. These challenges may be addressed through rational manipulations to control CAR T cell function. Here we examine the impact of cognate T cell antigen experience on subsequent CD8+ CAR T cell activity. Prior antigen encounter resulted in superior effector function against leukemia expressing low target antigen density at the expense of reduced proliferative capacity and susceptibility to dysfunction at limiting CAR doses. Distinctive temporal transcriptomic and epigenetic profiles in naive-derived and memory-derived CAR T cells identified RUNX family transcription factors as potential targets to augment the function of naive-derived CD8+ CAR T cells. RUNX2 overexpression enhanced antitumor efficacy of mouse CAR T cells, dependent on prior cell state, and heightened human CAR T cell functions. Our data demonstrate that prior antigen experience of CAR T cells determines functional attributes and amenability to transcription factor-mediated functional enhancement.

DOI: 10.1038/s41590-024-02034-1

Source: https://www.nature.com/articles/s41590-024-02034-1