Expansion and functional maturation of human tumor antigen-specific CD8+ T cells after vaccination with antigenic peptide.
Peptide-based vaccines are currently being tested for their ability to induce or augment tumor antigen (Ag)-specific CD8+ T-cell responses in cancer patients. Here we report that the frequency of circulating CD8+ T cells directed against the Melan-A/MART-1 Ag increased >20-fold in an HLA-A2 melanoma patient immunized repeatedly with the corresponding antigenic peptide, as assessed by staining with HLA-A2/peptide tetramers. Multiparameter flow cytometric analysis demonstrated that the increase in total Melan-A-specific cell number was accompanied by a marked increase in the proportion of the cells that expressed an activated/memory surface phenotype. As assessed by ELISPOT assays and intracellular staining, the absolute number of Melan-A-specific cells able to secrete IFN-gamma increased >50-fold upon vaccination. When tested directly after cell sorting on the basis of tetramer staining, Melan-A-specific cells were weakly cytolytic but became highly active after in vitro restimulation. Altogether, these results indicate that large numbers of functionally active tumor Ag-specific CD8+ T cells can be obtained and maintained at high levels after in vivo activation by repeated peptide-based vaccination.
Pittet
M J
MJ
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Speiser
D E
DE
Liénard
D
D
Valmori
D
D
Guillaume
P
P
Dutoit
V
V
Rimoldi
D
D
Lejeune
F
F
Cerottini
J C
JC
Romero
P
P
D000911:Antibodies, Monoclonal / Q000378:metabolism; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D019496:Cancer Vaccines / Q000737:chemistry*; D002455:Cell Division; D005434:Flow Cytometry; D053804:Granzymes; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D012697:Serine Endopeptidases / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases