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Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose

Lövgren, Tanja ; Baumgaertner, Petra ; Wieckowski, Sébastien ; Devêvre, Estelle ; Guillaume, Philippe ; Luescher, Immanuel ; Rufer, Nathalie ; Speiser, Daniel

In: Cancer Immunology, Immunotherapy, 2012, vol. 61, no. 6, p. 817-826

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    Title
    • Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose
    Author
    • Lövgren, Tanja. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    • Baumgaertner, Petra. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    • Wieckowski, Sébastien. University Hospital Center and University of Lausanne (CHUV), Lausanne, Switzerland
    • Devêvre, Estelle. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    • Guillaume, Philippe. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    • Luescher, Immanuel. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    • Rufer, Nathalie. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    • Speiser, Daniel. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Hôpital Orthopédique 05/1552, Av. Pierre-Decker 4, 1011, Lausanne, Switzerland
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:313459
    Summary
    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 0.5mg 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