title: Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases.
abstract: A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression.
authors.affiliation: de Duve Institute, Université Catholique de Louvain and Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Corbière
authors.forename: Jacques
authors.initials: J
authors.lastname: Chapiro
authors.forename: Vincent
authors.initials: V
authors.lastname: Stroobant
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ma
authors.forename: Christophe
authors.initials: C
authors.lastname: Lurquin
authors.forename: Bernard
authors.initials: B
authors.lastname: Lethé
authors.forename: Nicolas
authors.initials: N
authors.lastname: van Baren
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Van den Eynde
authors.forename: Thierry
authors.initials: T
authors.lastname: Boon
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D019496:Cancer Vaccines / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D006801:Humans; D020014:K562 Cells; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008954:Models, Biological; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012074:Remission Induction; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution / Q000276:immunology / Q000502:physiology; D047368:Tumor Burden
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta