CD137
T细胞受体
T细胞
细胞生物学
CD8型
癌症免疫疗法
免疫疗法
细胞毒性T细胞
癌症研究
嵌合抗原受体
CD3型
信号转导
生物
化学
抗原
免疫学
免疫系统
生物化学
体外
作者
Itziar Otano,Arantza Azpilikueta,Javier Glez-Vaz,Maite Álvarez,José Medina-Echeverz,Iván Cortés‐Domínguez,Carlos Ortiz‐de‐Solórzano,Peter Ellmark,Sara Fritzell,Gabriela Hernández-Hoyos,Michelle H. Nelson,María C. Ochoa,Elixabet Bolaños,Doina Cuculescu,Patricia Jaúregui,Sandra Sánchez-Gregorio,Iñaki Etxeberría,María E. Rodríguez-Ruiz,Miguel F. Sanmamed,Álvaro Teijeira,Pedro Berraondo,Ignacio Melero
标识
DOI:10.1038/s41467-021-27613-w
摘要
CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans.
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