肿瘤细胞治疗研究
英文原题：An NK-like CAR T cell transition in CAR T cell dysfunction.
嵌合抗原受体（CAR）T 细胞疗法在血液系统恶性肿瘤中取得了显著成功，但在实体瘤中仍无效，部分原因在于实体瘤微环境中 CAR T 细胞耗竭。
嵌合抗原受体（CAR）T细胞疗法在血液系统恶性肿瘤中取得显著成功，但在实体瘤中仍无效，部分原因是CAR-T细胞在实体瘤微环境中耗竭。为研究间皮素重定向CAR-T细胞在胰腺癌中的功能障碍，我们建立了一种可重复的持续抗原暴露模型，模拟T细胞耗竭的典型特征；并在体外及CAR-T细胞治疗患者中发现，CAR失调与CD8+ T细胞向NK样T细胞转变相关。此外，我们确定了定义CAR和TCR失调的基因特征，并发现包括SOX4和ID3在内的转录因子是CAR-T细胞耗竭的关键调节因子。我们的发现揭示了人CAR-T细胞的可塑性，并证明通过基因方式下调ID3和SOX4表达，可预防或延缓CAR-T细胞功能障碍，从而提高CAR-T治疗实体瘤的疗效。
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.
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