title: Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb.
abstract: Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.
authors.affiliation: Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;
authors.forename: Bettina
authors.initials: B
authors.lastname: Weigelin
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolaños
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Alvaro
authors.initials: A
authors.lastname: Teijeira
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Ivan
authors.initials: I
authors.lastname: Martinez-Forero
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Sara
authors.initials: S
authors.lastname: Labiano
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Aizea
authors.initials: A
authors.lastname: Morales-Kastresana
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: José I
authors.initials: JI
authors.lastname: Quetglas
authors.affiliation: Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;
authors.forename: Esther
authors.initials: E
authors.lastname: Wagena
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
authors.forename: Alfonso Rodríguez
authors.initials: AR
authors.lastname: Sánchez-Paulete
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511.
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain; imelero@unav.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D030161:Avian Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D020825:T-Box Domain Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D030161:Avian Proteins; C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D010047:Ovalbumin
keywords: CD137; Cytotoxic T lymphocyte; adoptive T-cell therapy; costimulation; immunotherapy