DeGolier Kole R, Danis Etienne, D'Antonio Marc, Cimons Jennifer, Yarnell Michael, Kedl Ross M, Kohler M Eric, Scott-Browne James P, Fry Terry J
Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nat Immunol. 2025 Jan;26(1):68-81. doi: 10.1038/s41590-024-02034-1. Epub 2025 Jan 2.
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.
尽管嵌合抗原受体（CAR）T细胞对B系恶性肿瘤有效，但CAR治疗后的复发很常见，且在其他肿瘤中的疗效有限。这些挑战可以通过合理调控来控制CAR T细胞功能加以解决。在此，我们研究同源T细胞抗原经历对后续CD8 CAR T细胞活性的影响。先前的抗原接触导致对表达低靶抗原密度的白血病具有更强的效应功能，但代价是增殖能力降低以及在CAR剂量有限时易发生功能障碍。初始来源和记忆来源的CAR T细胞中独特的时间转录组和表观遗传特征确定RUNX家族转录因子是增强初始来源的CD8 CAR T细胞功能的潜在靶点。RUNX2的过表达增强了小鼠CAR T细胞的抗肿瘤疗效，这取决于先前的细胞状态，并提高了人CAR T细胞的功能。我们的数据表明，CAR T细胞先前的抗原经历决定了其功能属性以及对转录因子介导的功能增强的适应性。
