Functional analysis of tumor-specific Th cell responses detected in melanoma patients after dendritic cell-based immunotherapy.
Recently, we have demonstrated that tumor-specific CD4+ Th cell responses can be rapidly induced in advanced melanoma patients by vaccination with peptide-loaded monocyte-derived dendritic cells. Most patients showed a T cell reactivity against a melanoma Ag 3 (MAGE-3) peptide (MAGE-3(243-258)), which has been previously found to be presented by HLA-DP4 molecules. To analyze the functional and specificity profile of this in vivo T cell response in detail, peptide-specific CD4+ T cell clones were established from postvaccination blood samples of two HLA-DP4 patients. These T cell clones recognized not only peptide-loaded stimulator cells but also dendritic cells loaded with a recombinant MAGE-3 protein, demonstrating that these T cells were directed against a naturally processed MAGE-3 epitope. The isolated CD4+ Th cells showed a typical Th1 cytokine profile upon stimulation. From the first patient several CD4+ T cell clones recognizing the antigenic peptide used for vaccination in the context of HLA-DP4 were obtained, whereas we have isolated from the second patient CD4+ T cell clones which were restricted by HLA-DQB1*0604. Analyzing a panel of truncated peptides revealed that the CD4+ T cell clones recognized different core epitopes within the original peptide used for vaccination. Importantly, a DP4-restricted T cell clone was stimulated by dendritic cells loaded with apoptotic or necrotic tumor cells and even directly recognized HLA class II- and MAGE-3-expressing tumor cells. Moreover, these T cells exhibited cytolytic activity involving Fas-Fas ligand interactions. These findings support that vaccination-induced CD4+ Th cells might play an important functional role in antitumor immunity.
Schultz
Erwin S
ES
Department of Dermatology, University Hospital of Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany. erwin.schultz@derma.imed.uni-erlangen.de
Schuler-Thurner
Beatrice
B
Stroobant
Vincent
V
Jenne
Lars
L
Berger
Thomas G
TG
Thielemanns
Kris
K
van der Bruggen
Pierre
P
Schuler
Gerold
G
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000633:toxicity; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism / Q000633:toxicity
D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006680:HLA Antigens; C072013:MAGEA3 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D019014:fas Receptor