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

Otano, Itziar (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),12 de Octubre University Hospital,Spanish National Cancer Research Center (CNIO),University of Navarra
Azpilikueta, Arantza (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),University of Navarra,Health Research Institute of Navarra (IDISNA)
Glez-Vaz, Javier (author)
University of Navarra,Health Research Institute of Navarra (IDISNA),Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
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Alvarez, Maite (author)
Health Research Institute of Navarra (IDISNA),University of Navarra,Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Medina-Echeverz, José (author)
Bavarian Nordic GmbH
Cortés-Domínguez, Ivan (author)
Health Research Institute of Navarra (IDISNA),University of Navarra
Ortiz-de-Solorzano, Carlos (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),University of Navarra,Health Research Institute of Navarra (IDISNA)
Ellmark, Peter (author)
Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH,Alligator Biosciences AB
Fritzell, Sara (author)
Alligator Biosciences AB
Hernandez-Hoyos, Gabriela (author)
Aptevo Therapeutics
Nelson, Michelle Hase (author)
Aptevo Therapeutics
Ochoa, María Carmen (author)
University Clinic of Navarra,Spanish Center for Biomedical Research Network in Oncology (CIBERONC),Health Research Institute of Navarra (IDISNA),University of Navarra
Bolaños, Elixabet (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),University Clinic of Navarra,Health Research Institute of Navarra (IDISNA)
Cuculescu, Doina (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),Health Research Institute of Navarra (IDISNA),University of Navarra
Jaúregui, Patricia (author)
Health Research Institute of Navarra (IDISNA),Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Sanchez-Gregorio, Sandra (author)
Health Research Institute of Navarra (IDISNA),University of Navarra,University Clinic of Navarra,Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Etxeberria, Iñaki (author)
Health Research Institute of Navarra (IDISNA),University of Navarra,Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Rodriguez-Ruiz, María E. (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),Health Research Institute of Navarra (IDISNA),University of Navarra,University Clinic of Navarra
Sanmamed, Miguel F. (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),University Clinic of Navarra,Health Research Institute of Navarra (IDISNA),University of Navarra
Teijeira, Álvaro (author)
University of Navarra,Health Research Institute of Navarra (IDISNA),University Clinic of Navarra,Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Berraondo, Pedro (author)
Spanish Center for Biomedical Research Network in Oncology (CIBERONC),University of Navarra,Health Research Institute of Navarra (IDISNA)
Melero, Ignacio (author)
Health Research Institute of Navarra (IDISNA),University of Navarra,Spanish National Cancer Research Center (CNIO),University Clinic of Navarra,12 de Octubre University Hospital,Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
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 (creator_code:org_t)
2021-12-15
2021
English.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
Related links:
http://dx.doi.org/10... (free)
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https://www.nature.c...
https://lup.lub.lu.s...
https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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