MAGE-6 encodes HLA-DRbeta1*0401-presented epitopes recognized by CD4+ T cells from patients with melanoma or renal cell carcinoma.
CD4+ T cells modulate the magnitude and durability of CTL responses in vivo and may serve as potent effector cells within the tumor microenvironment. The current study was undertaken to define novel epitopes from the broadly expressed tumor antigen MAGE-6 that are recognized by CD4+ T cells. We have combined the use of a HLA-DR4/peptide binding algorithm with the IFN-gamma enzyme-linked immunospot assay to identify four nonoverlapping sequences derived from the MAGE-6 protein that served as CD4+ T-cell epitopes in HLA-DR4+ donors. Strikingly, patients with active melanoma or renal cell carcinoma failed to secrete IFN-gamma in response to MAGE-6-derived epitopes, whereas both normal donors and cancer patients with no current evidence of disease were responsive, particularly after short-term in vitro stimulations with peptide-pulsed dendritic cells. Importantly, peptide-specific CD4+ T cells also recognized HLA-DRbeta1*0401+ tumor cells that constitutively expressed the MAGE-6 protein and autologous HLA-DRbeta1*0401+ dendritic cells transfected with MAGE-6 cDNA-elicited CD4+ T cells that reacted against individual peptide epitopes in vitro. These data suggest that MAGE-6-derived epitopes could serve as useful vaccine candidate components and may provide an immune-monitoring index of clinically important Th1-type immunity in patients with renal cell carcinoma or melanoma.
Tatsumi
Tomohide
T
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kierstead
Lisa S
LS
Ranieri
Elena
E
Gesualdo
Loreto
L
Schena
Francesco P
FP
Finke
James H
JH
Bukowski
Ronald M
RM
Brusic
Vladimir
V
Sidney
John
J
Sette
Alessandro
A
Logan
Theodore F
TF
Kasamon
Yvette L
YL
Slingluff
Craig L
CL
Kirkwood
John M
JM
Storkus
Walter J
WJ
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000465:Algorithms; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D020128:Inhibitory Concentration 50; D007371:Interferon-gamma / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D014162:Transfection
D000951:Antigens, Neoplasm; D000939:Epitopes; D006684:HLA-DR Antigens; C095203:MAGEA6 protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D007371:Interferon-gamma