Scientific publications

CD137 (4-1BB) costimulation of CD8 + T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation

Dec 15, 2021 | Magazine: 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.

CITATION  Nat Commun. 2021 Dec 15;12(1):7296.  doi: 10.1038/s41467-021-27613-w

Our authors

Arantza Azpilicueta Lusarreta
Maite Álvarez Rodríguez
Iván Cortés Domínguez
Elixabet Bolaños Mateo
Sandra Sánchez Gregorio