2. Academic Validation
  3. CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

  • Sci Adv. 2023 Aug 18;9(33):eadf6692. doi: 10.1126/sciadv.adf6692.
Javier Glez-Vaz 1 2,  Arantza Azpilikueta 1 2,  María C Ochoa 1 2 3 4,  Irene Olivera 1 2,  Gabriel Gomis 1,  Asunta Cirella 1 2 3,  Carlos Luri-Rey 1 2,  Maite Álvarez 1 2 4,  Jose L Pérez-Gracia 3,  Sergio Ciordia 5,  Iñaki Eguren-Santamaria 1 3,  Raluca Alexandru 3,  Pedro Berraondo 1 2 4,  Carlos de Andrea 3,  Álvaro Teijeira 1 2 4,  Fernando Corrales 5,  Juan M Zapata 6 7,  Ignacio Melero 1 2 3 4 8
Affiliations

Affiliations

  • 1 Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.
  • 2 Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
  • 3 Departments of Immunology-Immunotherapy, Pathology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 4 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 5 Functional Proteomics Laboratory, CNB-CSIC, Proteored-ISCIII, Madrid, Spain.
  • 6 Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM, Madrid, Spain.
  • 7 Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain.
  • 8 Nuffield Department of Medicine, University of Oxford, Oxford, UK.
PMID: 37595047 DOI: 10.1126/sciadv.adf6692
Abstract

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in Cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in Cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137's cytoplasmic tail.

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