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: Tanja Lövgren, Petra Baumgaertner, Sébastien Wieckowski, Estelle Devêvre, Philippe Guillaume, Immanuel Luescher, Nathalie Rufer, Daniel E Speiser
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 61 Issue 6 Pg. 817-26 (Jun 2012) ISSN: 1432-0851 [Electronic] Germany
• PMID: 22080404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• Cytokines
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• MART-1 Antigen
• Oligodeoxyribonucleotides
• Peptides
• ProMune

Topics

• Cancer Vaccines (administration & dosage, immunology)
• Chemotherapy, Adjuvant
• Cytokines (biosynthesis)
• Dose-Response Relationship, Drug
• Female
• HLA-A2 Antigen (immunology)
• Humans
• MART-1 Antigen (immunology)
• Male
• Melanoma (immunology, pathology, therapy)
• Neoplasm Staging
• Oligodeoxyribonucleotides (administration & dosage, immunology)
• Peptides (administration & dosage, immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Vaccination