Article: article from journal or magazin.
Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose.
Cancer Immunology, Immunotherapy
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
In mice, vaccination with high peptide doses generates higher frequencies of specific CD8+ T cells, but with lower avidity compared to vaccination with lower peptide doses. To investigate the impact of peptide dose on CD8+ T cell responses in humans, melanoma patients were vaccinated with 0.1 or 0.5 mg Melan-A/MART-1 peptide, mixed with CpG 7909 and Incomplete Freund's adjuvant. Neither the kinetics nor the amplitude of the Melan-A-specific CD8+ T cell responses differed between the two vaccination groups. Also, CD8+ T cell differentiation and cytokine production ex vivo were similar in the two groups. Interestingly, after low peptide dose vaccination, Melan-A-specific CD8+ T cells showed enhanced degranulation upon peptide stimulation, as assessed by CD107a upregulation and perforin release ex vivo. In accordance, CD8+ T cell clones derived from low peptide dose-vaccinated patients showed significantly increased degranulation and stronger cytotoxicity. In parallel, Melan-A-specific CD8+ T cells and clones from low peptide dose-vaccinated patients expressed lower CD8 levels, despite similar or even stronger binding to tetramers. Furthermore, CD8+ T cell clones from low peptide dose-vaccinated patients bound CD8 binding-deficient tetramers more efficiently, suggesting that they may express higher affinity TCRs. We conclude that low peptide dose vaccination generated CD8+ T cell responses with stronger cytotoxicity and lower CD8 dependence.
Cancer Vaccines/administration & dosage, Cancer Vaccines/immunology, Chemotherapy, Adjuvant, Cytokines/biosynthesis, Dose-Response Relationship, Drug, Female, HLA-A2 Antigen/immunology, Humans, MART-1 Antigen/immunology, Male, Melanoma/immunology, Melanoma/pathology, Neoplasm Staging, Oligodeoxyribonucleotides/administration & dosage, Oligodeoxyribonucleotides/immunology, Peptides/administration & dosage, Peptides/immunology, T-Lymphocytes, Cytotoxic/immunology, Vaccination
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