Tumor antigen-specific FOXP3+ CD4 T cells identified in human metastatic melanoma: peptide vaccination results in selective expansion of Th1-like counterparts

Cancer Res. 2009 Oct 15;69(20):8085-93. doi: 10.1158/0008-5472.CAN-09-2226. Epub 2009 Oct 6.

Abstract

We have previously shown that vaccination of HLA-A2 metastatic melanoma patients with the analogue Melan-A(26-35(A27L)) peptide emulsified in a mineral oil induces ex vivo detectable specific CD8 T cells. These are further enhanced when a TLR9 agonist is codelivered in the same vaccine formulation. Interestingly, the same peptide can be efficiently recognized by HLA-DQ6-restricted CD4 T cells. We used HLA-DQ6 multimers to assess the specific CD4 T-cell response in both healthy individuals and melanoma patients. We report that the majority of melanoma patients carry high frequencies of naturally circulating HLA-DQ6-restricted Melan-A-specific CD4 T cells, a high proportion of which express FOXP3 and proliferate poorly in response to the cognate peptide. Upon vaccination, the relative frequency of multimer+ CD4 T cells did not change significantly. In contrast, we found a marked shift to FOXP3-negative CD4 T cells, accompanied by robust CD4 T-cell proliferation upon in vitro stimulation with cognate peptide. A concomitant reduction in TCR diversity was also observed. This is the first report on direct ex vivo identification of antigen-specific FOXP3+ T cells by multimer labeling in cancer patients and on the direct assessment of the impact of peptide vaccination on immunoregulatory T cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, Neoplasm / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / therapeutic use
  • Case-Control Studies
  • Female
  • Forkhead Transcription Factors / metabolism*
  • HLA-A2 Antigen / immunology
  • HLA-DQ Antigens / immunology
  • HLA-DQ Antigens / metabolism
  • Humans
  • Immunotherapy
  • MART-1 Antigen
  • Male
  • Melanoma / immunology*
  • Melanoma / secondary
  • Melanoma / therapy
  • Middle Aged
  • Neoplasm Proteins / immunology*
  • Peptide Fragments / immunology*
  • Receptors, Antigen, T-Cell
  • Th1 Cells / immunology*
  • Vaccination

Substances

  • Antigens, Neoplasm
  • Cancer Vaccines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HLA-A2 Antigen
  • HLA-DQ Antigens
  • MART-1 Antigen
  • MLANA protein, human
  • Neoplasm Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell