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

Author:

Glez-Vaz Javier12ORCID,Azpilikueta Arantza12ORCID,Ochoa María C.1234ORCID,Olivera Irene12ORCID,Gomis Gabriel1ORCID,Cirella Asunta123ORCID,Luri-Rey Carlos12ORCID,Álvarez Maite124ORCID,Pérez-Gracia Jose L.3ORCID,Ciordia Sergio5ORCID,Eguren-Santamaria Iñaki13ORCID,Alexandru Raluca3ORCID,Berraondo Pedro124ORCID,de Andrea Carlos3ORCID,Teijeira Álvaro124ORCID,Corrales Fernando5,Zapata Juan M.67,Melero Ignacio12348ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Cited by 5 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3