title: Dacarbazine treatment before peptide vaccination enlarges T-cell repertoire diversity of melan-a-specific, tumor-reactive CTL in melanoma patients.
abstract: Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)-specific, tumor-reactive, long-lasting effector-memory CD8(+) T cells after the administration of dacarbazine (DTIC) 1 day before peptide vaccination in melanoma patients. Global transcriptional analysis revealed a DTIC-induced activation of genes involved in the immune response and leukocyte activation. To identify the possible mechanisms underlying this improved immune response, we have compared the endogenous and the treatment-induced anti-Melan-A response at the clonal level in patients treated with the vaccine alone or with DTIC plus vaccine. We report a progressive widening of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, only in Melan-A-specific T-cell clones of patients treated with chemoimmunotherapy, with a trend toward longer survival. Differently, patients treated with vaccine alone showed a tendency to narrowing the TCR repertoire diversity, accompanied by a decrease of tumor lytic activity in one patient. Collectively, our findings indicate that DTIC plus vaccination shapes the TCR repertoire in terms of diversity and antitumor response, suggesting that this combined therapy could be effective in preventing melanoma relapse.
authors.affiliation: Laboratory of Immunology, Regina Elena National Cancer Institute, Via delle Messi d'oro 156, 00158 Rome, Italy.
authors.forename: Belinda
authors.initials: B
authors.lastname: Palermo
authors.forename: Duilia
authors.initials: D
authors.lastname: Del Bello
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sottini
authors.forename: Federico
authors.initials: F
authors.lastname: Serana
authors.forename: Claudia
authors.initials: C
authors.lastname: Ghidini
authors.forename: Novella
authors.initials: N
authors.lastname: Gualtieri
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferraresi
authors.forename: Caterina
authors.initials: C
authors.lastname: Catricalà
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Proietti
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Luisa
authors.initials: L
authors.lastname: Imberti
authors.forename: Paola
authors.initials: P
authors.lastname: Nisticò
mesh_terms: D000915:Antibody Affinity; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000627:therapeutic use*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D020014:K562 Cells; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D009363:Neoplasm Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D022223:Vaccines, Subunit; D003606:Dacarbazine