美国宾夕法尼亚大学 Carl H. June，Regina M. Young 和 Shelley L. Berger 三位研究人员共同合作取得了重要的进展，他们研究发现 CAR T 细胞功能障碍与 CAR T 细胞向自然杀伤样（NK-like）CAR T 细胞的转变相关。这项工作于2021年12月2日在线发表在《细胞》杂志上。
研究人员为了探讨胰腺癌间皮素重定向嵌合抗原受体（Chimeric antigen receptor, CAR) T 细胞的功能障碍，建立了一个连续抗原暴露的高效模型，该模型概述了 T 细胞耗竭的标志性特征，发现无论是在体外还是在 CAR T 细胞患者中，CAR 的失调都与 CD8+ T 细胞到 NK-like T 细胞的转变相关。
此外，研究人员明确了定义 CAR 和 TCR 调节异常的基因特征，一些转录因子包括 SOX4 和 ID3 都是 CAR T 细胞耗竭的关键调控因子。他们的发现阐明了人类 CAR T 细胞的可塑性，并表明下调 ID3 和 SOX4 的表达可以预防或延迟 CAR T 细胞功能障碍，从而能够提高实体瘤中 CAR T 细胞治疗的效果。
据了解，CAR T 细胞治疗法在血液恶性肿瘤中已经取得了显著的成功，但在实体肿瘤中仍然无效，部分原因是 CAR T 细胞在实体肿瘤微环境中消耗的比较快。
附：英文原文
Title: An NK-like CAR T cell transition in CAR T cell dysfunction
Author: Charly R. Good, M. Angela Aznar, Shunichiro Kuramitsu, Parisa Samareh, Sangya Agarwal, Greg Donahue, Kenichi Ishiyama, Nils Wellhausen, Austin K. Rennels, Yujie Ma, Lifeng Tian, Sonia Guedan, Katherine A. Alexander, Zhen Zhang, Philipp C. Rommel, Nathan Singh, Karl M. Glastad, Max W. Richardson, Keisuke Watanabe, Janos L. Tanyi, Mark H. O’Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June
Issue&Volume: 2021-12-02
Abstract: Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success inhematological malignancies but remains ineffective in solid tumors, due in part toCAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction ofmesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust modelof continuous antigen exposure that recapitulates hallmark features of T cell exhaustionand discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-likeT cell transition. Furthermore, we identify a gene signature defining CAR and TCRdysregulation and transcription factors, including SOX4 and ID3 as key regulatorsof CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cellsand demonstrate that genetic downmodulation of ID3 and SOX4 expression can improvethe efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T celldysfunction.
DOI: 10.1016/j.cell.2021.11.016
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01331-3