title: Tumor antigen-specific FOXP3+ CD4 T cells identified in human metastatic melanoma: peptide vaccination results in selective expansion of Th1-like counterparts.
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.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research Ltd, Lausanne Branch, Hôpital Orthopédique, Lausanne, Switzerland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Jandus
authors.forename: Gilles
authors.initials: G
authors.lastname: Bioley
authors.forename: Danijel
authors.initials: D
authors.lastname: Dojcinovic
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wieckowski
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Tiercy
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell; D018417:Th1 Cells / Q000276:immunology*; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015789:HLA-A2 Antigen; D006683:HLA-DQ Antigens; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell