CD5 缺失增强了过继性 T 细胞疗法的抗肿瘤活性。
CD5 deletion enhances the antitumor activity of adoptive T cell therapies.
发表日期：2024 Jul 19
作者：
Ruchi P Patel, Guido Ghilardi, Yunlin Zhang, Yi-Hao Chiang, Wei Xie, Puneeth Guruprasad, Ki Hyun Kim, Inkook Chun, Mathew G Angelos, Raymone Pajarillo, Seok Jae Hong, Yong Gu Lee, Olga Shestova, Carolyn Shaw, Ivan Cohen, Aasha Gupta, Trang Vu, Dean Qian, Steven Yang, Aditya Nimmagadda, Adam E Snook, Nicholas Siciliano, Antonia Rotolo, Arati Inamdar, Jaryse Harris, Ositadimma Ugwuanyi, Michael Wang, Alberto Carturan, Luca Paruzzo, Linhui Chen, Hatcher J Ballard, Tatiana Blanchard, Chong Xu, Mohamed Abdel-Mohsen, Khatuna Gabunia, Maria Wysocka, Gerald P Linette, Beatriz Carreno, David M Barrett, David T Teachey, Avery D Posey, Daniel J Powell, C Tor Sauter, Stefano Pileri, Vinodh Pillai, John Scholler, Alain H Rook, Stephen J Schuster, Stefan K Barta, Patrizia Porazzi, Marco Ruella
来源：
Science Immunology
摘要：
大多数接受美国食品和药物管理局 (FDA) 批准的嵌合抗原受体 (CAR) T 细胞治疗的患者最终都会经历疾病进展。此外，CAR T 细胞还不能治愈实体癌和一些预后极差的 T 细胞淋巴瘤等血液恶性肿瘤。过继性 T 细胞免疫疗法临床成功的主要障碍之一是 CAR T 细胞功能障碍以及输注后缺乏扩增和/或持久性。在这项研究中，我们发现 CD5 抑制 CAR T 细胞活化，并且使用 CRISPR-Cas9 敲除 (KO) CD5 可增强 CAR T 细胞在多种血液学和实体癌模型中的抗肿瘤作用。从机制上讲，CD5 KO 可增强 T 细胞效应功能，并具有增强的细胞毒性、体内扩增和持久性，并且在临床前模型中没有明显的毒性。这些发现表明 CD5 是 T 细胞功能的关键抑制剂，也是增强 T 细胞治疗的潜在临床靶点。
Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.