title: Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors.
abstract: Treatment of advanced, poorly immunogenic tumors in animal models, considered the closest simulation available thus far for conditions observed in cancer patients, remains a major challenge for cancer immunotherapy. We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen-specific cytotoxic T lymphocyte responses. In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti-4-1BB mAb. We provide evidence that immunological ignorance, rather than anergy or deletion, of tumor antigen--specific CTLs during the progressive growth of tumors prevents costimulation by anti-4-1BB mAb. Breaking CTL ignorance by immunization with a tumor antigen-derived peptide, although insufficient to stimulate a curative CTL response, is necessary for anti--4-1BB mAb to induce a CTL response leading to the regression of established tumors. Our results suggest a new approach for immunotherapy of human cancers.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Wilcox
authors.forename: Dallas B
authors.initials: DB
authors.lastname: Flies
authors.forename: Gefeng
authors.initials: G
authors.lastname: Zhu
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Chapoval
authors.forename: Scott E
authors.initials: SE
authors.lastname: Strome
authors.forename: Larry R
authors.initials: LR
authors.lastname: Pease
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD; D000951:Antigens, Neoplasm / Q000378:metabolism*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D009856:Oncogene Proteins, Viral / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C059731:oncogene protein E7, Human papillomavirus type 16