Peptide-specific CD8+ T-cell evolution in vivo: Response to peptide vaccination with Melan-A/MART-1

Elke Jäger, Hauni Höhn, Artje Necker, Reinhold Förster, Julia Karbach, Kirsten Freitag, Claudia Neukirch, Chiara Castelli, Russell D. Salter, Alaxander Knuth, Markus J. Maeurer

Research output: Contribution to journalArticlepeer-review

Abstract

Monitoring of CD8+ T-cell responses in cancer patients during peptide vaccination is essential to provide useful surrogate markers and to demonstrate vaccine efficacy. We have longitudinally followed CD8+ T-cell responses in 3 melanoma patients who were immunized with peptides derived from Melan-A/MART-I. Recombinant HLA-A2 tetramers loaded with the naturally presented Melan-AJMART-I nonamer peptide (AAGIGILTV) and the Melan-A/MART-I analog (ELAGIGILTV) were used in combination with phenotypical analysis for different T-cell subsets including naive T cells, effector T cells, "true memory" T cells and "memory effector" T cells, based on CD45RA/RO and CCR7-expression. At least in a single patient, T cells binding to the AAGIGILTV epitope were detected in naive, precursor (CD45RA+/CCR7+) CD8+ T cells, and CD8+ T cells binding to the analog ELAGIGILTV peptide were identified in the terminally differentiated (CD45RA+/CCR7-) T-cell subset. Molecular and functional analysis of tetramer-binding T cells revealed that the T-cell receptor (TCR) repertoire was oligo/polyclonal in AAGIGILTV-reactive T cells, but different and restricted to a few TCR clonotypes in ELAGIGILTV-reactive T cells prior to vaccination. The TCR repertoire reactive with Melan-AJMART-I peptide epitopes was broadened during vaccination and exhibited a different profile of cytokine release after specific stimulation: tetramer-binding T cells from 2/3 patients secreted granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-γ but not interleukin-2 (IL-2) in response to Melan-A/MART-I peptides. In the third patient, tetramer-binding T cells secreted IL-2 exclusively. Our results show that T-cell responses to peptide vaccination consist of different T-cell subsets associated with different effector functions. Complementary analysis for TCR CDR3 and cytokine profiles may be useful to define the most effective CD8+ T-cell population induced by peptide vaccination.

Original languageEnglish
Pages (from-to)376-388
Number of pages13
JournalInternational Journal of Cancer
Volume98
Issue number3
DOIs
Publication statusPublished - Mar 20 2002

Keywords

  • Immunotherapy
  • Melanoma
  • T cells
  • TCR
  • Vaccination

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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