Abstract 614: CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

Abstract CD137 (4-1BB) is a member of the TNFR family, whose expression is induced on antigen-primed T cells and that mediates potent 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 polyprotein 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 proteasomal degradation of cIAPs and transfecting dominant-negative variants of cIAPs. Importantly, antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models. Citation Format: Javier Glez-Vaz, Arantza Azpilikueta, Maria Carmen Ochoa, Irene Olivera, Gabriel Gomis, Asunta Cirella, Carlos Luri-Rey, Maite Álvarez, Sergio Ciordia, Pedro Berraondo, Álvaro Teijeira, Fernando Corrales, Juan M Zapata, Ignacio Melero. CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 614.