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.
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Acknowledgments
We are obliged to patients and blood donors for their dedicated collaboration. We gratefully acknowledge L. J. Old, J. O’Donnell-Tormey, E. W. Hoffman, O. Michielin, A. Auteri, G. Berthod and K. Homicsko for their contributions, H. R. MacDonald, P. Romero, J. Skipper, H. F. Oettgen and H. Märki, for support, and P. Schneider, T. Brunner, E. Wattrang, H. Bouzourene, L. Baitsch, M. Braun, C. Meyer, A. Legat, D. Labes, M. Iancu, B. Gupta, J. -P. Rivals, L. Derré, C. Touvrey, K. Servis, L. Pan and R. Venhaus for collaboration and advice. We thank J. -M. Tiercy and V. Aubert for HLA typing, and Pfizer and Coley Pharmaceutical Group (USA) for providing CpG 7909 (PF-3512676). We are also thankful for the excellent help of C. Beauverd, C. Geldhof, L. Cagnon, L. Leyvraz, N. Montandon, E. Cuennet, and M. van Overloop. The study was supported by Swiss Cancer League grant 02279-08-2008, Swiss National Science Foundation, Swiss National Center of Competence in Research (NCCR) Molecular Oncology, Ludwig Institute for Cancer Research, Cancer Research Institute (USA), Cancer Vaccine Collaborative, and Atlantic Philanthropies (USA).
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Lövgren, T., Baumgaertner, P., Wieckowski, S. et al. Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose. Cancer Immunol Immunother 61, 817–826 (2012). https://doi.org/10.1007/s00262-011-1140-1
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DOI: https://doi.org/10.1007/s00262-011-1140-1