Dacarbazine treatment before peptide vaccination enlarges T-cell repertoire diversity of melan-a-specific, tumor-reactive CTL in melanoma patients.
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.
Palermo
Belinda
B
Laboratory of Immunology, Regina Elena National Cancer Institute, Via delle Messi d'oro 156, 00158 Rome, Italy.
Del Bello
Duilia
D
Sottini
Alessandra
A
Serana
Federico
F
Ghidini
Claudia
C
Gualtieri
Novella
N
Ferraresi
Virginia
V
Catricalà
Caterina
C
Belardelli
Filippo
F
Proietti
Enrico
E
Natali
Pier Giorgio
PG
Imberti
Luisa
L
Nisticò
Paola
P
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
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