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

15-dic-2021 | Revista: Nature Communications

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

Nuestros autores

Arantza Azpilicueta Lusarreta
Maite Álvarez Rodríguez
Iván Cortés Domínguez