title: T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes.
abstract: Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients.
authors.affiliation: Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona 31008, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Martinez-Forero
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolaños-Mateo
authors.forename: Estanislao
authors.initials: E
authors.lastname: Nistal-Villan
authors.forename: Asis
authors.initials: A
authors.lastname: Palazon
authors.forename: Alvaro
authors.initials: A
authors.lastname: Teijeira
authors.forename: Gema
authors.initials: G
authors.lastname: Perez-Chacon
authors.forename: Aizea
authors.initials: A
authors.lastname: Morales-Kastresana
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.forename: Juan M
authors.initials: JM
authors.lastname: Zapata
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D011992:Endosomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D025821:Polyubiquitin / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D025821:Polyubiquitin