CD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
(2021) In Nature Communications 12(1).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2021-12-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 12
- issue
- 1
- article number
- 7296
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85121338417
- pmid:34911975
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-021-27613-w
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021, The Author(s).
- id
- ca6e18f0-8052-489a-b7cc-7c04728ddb19
- date added to LUP
- 2022-01-26 15:40:12
- date last changed
- 2024-04-20 19:30:19
@article{ca6e18f0-8052-489a-b7cc-7c04728ddb19,
abstract = {{<p>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.</p>}},
author = {{Otano, Itziar and Azpilikueta, Arantza and Glez-Vaz, Javier and Alvarez, Maite and Medina-Echeverz, José and Cortés-Domínguez, Ivan and Ortiz-de-Solorzano, Carlos and Ellmark, Peter and Fritzell, Sara and Hernandez-Hoyos, Gabriela and Nelson, Michelle Hase and Ochoa, María Carmen and Bolaños, Elixabet and Cuculescu, Doina and Jaúregui, Patricia and Sanchez-Gregorio, Sandra and Etxeberria, Iñaki and Rodriguez-Ruiz, María E. and Sanmamed, Miguel F. and Teijeira, Álvaro and Berraondo, Pedro and Melero, Ignacio}},
issn = {{2041-1723}},
language = {{eng}},
month = {{12}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{CD137 (4-1BB) costimulation of CD8<sup>+</sup> T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation}},
url = {{http://dx.doi.org/10.1038/s41467-021-27613-w}},
doi = {{10.1038/s41467-021-27613-w}},
volume = {{12}},
year = {{2021}},
}