Dataset Information

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

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. 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 towards the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC-mimetics that trigger cIAPs 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.

INSTRUMENT(S): Orbitrap Exploris 240

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Sergio Ciordia

LAB HEAD: Ignacio Melero Bermejo

PROVIDER: PXD042585 | Pride | 2024-05-24

REPOSITORIES: Pride

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

Glez-Vaz Javier J Azpilikueta Arantza A Ochoa María C MC Olivera Irene I Gomis Gabriel G Cirella Asunta A Luri-Rey Carlos C Álvarez Maite M Pérez-Gracia Jose L JL Ciordia Sergio S Eguren-Santamaria Iñaki I Alexandru Raluca R Berraondo Pedro P de Andrea Carlos C Teijeira Álvaro Á Corrales Fernando F Zapata Juan M JM Melero Ignacio I

Science advances 20230818 33

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 costimulatio ...[more]

PMID: 37595047

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