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

Itziar Otano (), Arantza Azpilikueta, Javier Glez-Vaz, Maite Alvarez, José Medina-Echeverz, Ivan Cortés-Domínguez, Carlos Ortiz- de-Solorzano, Peter Ellmark, Sara Fritzell, Gabriela Hernandez-Hoyos, Michelle Hase Nelson, María Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jaúregui, Sandra Sanchez-Gregorio, Iñaki Etxeberria, María E. Rodriguez-Ruiz, Miguel F. Sanmamed, Álvaro Teijeira, Pedro Berraondo and Ignacio Melero ()
Additional contact information
Itziar Otano: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Arantza Azpilikueta: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Javier Glez-Vaz: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Maite Alvarez: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
José Medina-Echeverz: Bavarian Nordic GmbH
Ivan Cortés-Domínguez: Navarra Institute for Health Research (IDISNA)
Carlos Ortiz- de-Solorzano: Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Peter Ellmark: Alligator Bioscience
Sara Fritzell: Alligator Bioscience
Gabriela Hernandez-Hoyos: Aptevo Therapeutics
Michelle Hase Nelson: Aptevo Therapeutics
María Carmen Ochoa: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Elixabet Bolaños: Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Doina Cuculescu: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Patricia Jaúregui: Spanish Center for Biomedical Research Network in Oncology (CIBERONC)
Sandra Sanchez-Gregorio: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Iñaki Etxeberria: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
María E. Rodriguez-Ruiz: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Miguel F. Sanmamed: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Álvaro Teijeira: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Pedro Berraondo: Program of Immunology and Immunotherapy, Cima Universidad de Navarra
Ignacio Melero: Program of Immunology and Immunotherapy, Cima Universidad de Navarra

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27613-w

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