Publicaciones científicas
CD137 (4-1BB) costimulation of CD8 + T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
Itziar Otano # 1 2 3 , Arantza Azpilikueta # 4 5 6 , Javier Glez-Vaz 4 5 6 , Maite Alvarez 4 5 6 , José Medina-Echeverz 7 , Ivan Cortés-Domínguez 6 8 , Carlos Ortiz-de-Solorzano 5 6 8 , Peter Ellmark 9 10 , Sara Fritzell 9 , Gabriela Hernandez-Hoyos 11 , Michelle Hase Nelson 11 , María Carmen Ochoa 4 5 6 12 , Elixabet Bolaños 5 6 12 , Doina Cuculescu 4 5 6 , Patricia Jaúregui 5 6 , Sandra Sanchez-Gregorio 4 5 6 12 , Iñaki Etxeberria 4 5 6 , María E Rodriguez-Ruiz 4 5 6 13 , Miguel F Sanmamed 4 5 6 14 , Álvaro Teijeira 4 5 6 12 , Pedro Berraondo 4 5 6 , Ignacio Melero 15 16 17 18 19 20
Abstract
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.
CITA DEL ARTÍCULO Nat Commun. 2021 Dec 15;12(1):7296. doi: 10.1038/s41467-021-27613-w