title: Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose.
abstract: 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.
authors.affiliation: Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, Lausanne, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Lövgren
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wieckowski
authors.forename: Estelle
authors.initials: E
authors.lastname: Devêvre
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Immanuel
authors.initials: I
authors.lastname: Luescher
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D017024:Chemotherapy, Adjuvant; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D058965:MART-1 Antigen / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; D009838:Oligodeoxyribonucleotides; D010455:Peptides; C483020:ProMune
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