Weill Cornell Graduate School of Medical Sciences, New York, New York.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Immunol Res. 2020 Jun;8(6):732-742. doi: 10.1158/2326-6066.CIR-19-0908. Epub 2020 Mar 25.
Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Previous studies have identified a role for sustained CAR CD3ζ signaling in CAR T-cell dysfunction. Here, we demonstrate a mechanism that drives dysfunction in CAR T cells through excessive costimulation. Fully activated CD19-targeted CAR T cells were rendered dysfunctional upon stimulation with both endogenous CD28 stimulation and CAR-mediated CD28 costimulation. Costimulation-driven dysfunction of CAR T cells was demonstrated in a syngeneic immunocompetent mouse model, in which CAR T cells were activated with signals 1 (CD3ζ), 2 (CD28), and 3 (IL12). Thus, we show that CAR T-cell dysfunction can be driven through excessive CD28 and 4-1BB costimulation..
虽然针对某些血液系统恶性肿瘤的 CD19 靶向嵌合抗原受体 (CAR) T 细胞治疗已经观察到临床反应，但疾病的高复发率突出表明需要了解和改善 CAR T 细胞失效的机制。由于 T 细胞功能障碍被认为导致 CAR T 细胞治疗失败，因此了解哪些机制导致 T 细胞进入这种功能障碍状态可能有助于设计有效的 CAR T 细胞。功能失调的 CAR T 细胞表现为上调的抑制性受体和降低的细胞溶解能力。先前的研究已经确定持续的 CAR CD3ζ 信号在 CAR T 细胞功能障碍中起作用。在这里，我们通过过度共刺激证明了一种导致 CAR T 细胞功能障碍的机制。在受到内源性 CD28 刺激和 CAR 介导的 CD28 共刺激的刺激下，完全激活的 CD19 靶向 CAR T 细胞变得功能失调。在同种异体免疫活性小鼠模型中证明了 CAR T 细胞的共刺激驱动功能障碍，其中 CAR T 细胞通过信号 1（CD3ζ）、信号 2（CD28）和信号 3（IL12）激活。因此，我们表明 CAR T 细胞功能障碍可通过过度的 CD28 和 4-1BB 共刺激驱动。
