Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

嵌合抗原受体 (CAR) T 细胞疗法在血液恶性肿瘤中取得了显着的成功，但在实体瘤中仍然无效，部分原因是实体瘤微环境中的 CAR T 细胞耗竭。为了研究胰腺癌中间皮素重定向 CAR T 细胞的功能障碍，我们建立了一个稳健的连续抗原暴露模型，该模型概括了 T 细胞耗竭的标志性特征，并在体外发现在 CAR T 细胞患者中，CAR 失调与 CD8+ T 细胞向 NK 样 T 细胞的转变有关。此外，我们确定了定义 CAR 和 TCR 失调和转录因子的基因特征，包括 SOX4 和 ID3 作为 CAR T 细胞耗竭的关键调节因子。我们的研究结果揭示了人类 CAR T 细胞的可塑性，并证明 ID3 和 SOX4 表达的基因下调可以通过预防或延迟 CAR T 细胞功能障碍来提高 CAR T 细胞治疗实体瘤的疗效。