CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects
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
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 human and mouse T lymphocyte costimulation. Functional evidence was substantiated with SMAC mimetics triggering cIAP degradation and 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.