Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27613-w
Keywords
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Funding
- Aptevo Therapeutics
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2014-52361-R, SAF 201783267-C2-1R, PID2020-112892RB-100]
- Cancer Research Institute under the CRI-CLIP
- Asociacion Espanola Contra el Cancer (AECC) Foundation [GCB15152947MELE]
- Instituto de Salud Carlos III [TRS-2016-00000371, PI14/01686, PI13/00207, PI16/00668, PI19/01128]
- European Union (ERDF, A way to make Europe)
- European Commission [635122]
- Gobierno de Navarra Proyecto LINTERNA [0011-1411]
- Mark Foundation
- Fundacion BBVA
- AECC
- Spanish Ministry of Science of Innovation and Universities [RTI2018-094494-B-C22]
- la Caixa Banking Foundation [LCF/BQ/LR18/11640014]
- Miguel Servet contract from Instituto de Salud Carlos III, Fondo de Investigacion Sanitaria (Spain)
- Alligator Bioscience
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This study demonstrates that providing CD137 costimulation in-cis with the TCR-CD3-ligating cell is more effective in promoting T cell activation, proliferation, survival, and function compared to providing it in-trans. This finding is important for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently in clinical trials.
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-kappa B 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. Costimulation has been shown to be required for optimal activation of T cells and it could be delivered either in trans with respect to the source of CD3-TCR ligation or in cis on the same cell. Here the authors show that CD137 costimulation is more effective when delivered in cis to enhance T cell proliferation and activation.
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