Multiepitope CD8(+) T cell response to a NY-ESO-1 peptide vaccine results in imprecise tumor targeting.
The cancer-testis antigen NY-ESO-1 is one of the most promising candidates for generic vaccination of cancer patients. Here we analyzed the CD8(+) T cell response to a NY-ESO-1 peptide vaccine composed of the two previously defined peptides 157-165 and 157-167, administered with GM-CSF as a systemic adjuvant. The NY-ESO-1 peptide vaccine elicited a CD8(+) T cell response directed against multiple distinct epitopes in the 157-167 region, as revealed by using A2/peptide multimers incorporating overlapping A2 binding peptides in this region. However, only a minor fraction of the elicited CD8(+) T cells, namely those recognizing the peptide 157-165 with sufficiently high functional avidity, recognized the naturally processed target on NY-ESO-1(+) tumor cells. In contrast, the majority of peptide 157-165-specific CD8(+) T cells exhibited lower functional avidity and no tumor reactivity. In addition, vaccine-elicited CD8(+) T cells specific for other overlapping epitopes in the 157-167 region failed to significantly recognize NY-ESO-1-expressing tumor targets. Thus, because of the complexity of the CD8(+) T cell repertoire that can be elicited by vaccination with synthetic peptides, a precise definition of the targeted epitope, and hence, of the corresponding peptide to be used as immunogen, is required to ensure a precise tumor targeting.
Dutoit
Valérie
V
Ludwig Institute Clinical Trial Center, New York Branch at Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Taub
Robert N
RN
Papadopoulos
Kyriakos P
KP
Talbot
Susan
S
Keohan
Mary-Louise
ML
Brehm
Michelle
M
Gnjatic
Sacha
S
Harris
Paul E
PE
Bisikirska
Brygida
B
Guillaume
Philippe
P
Cerottini
Jean-Charles
JC
Hesdorffer
Charles S
CS
Old
Lloyd J
LJ
Valmori
Danila
D
D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007890:Leiomyosarcoma / Q000276:immunology / Q000628:therapy; D008297:Male; D008565:Membrane Proteins; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D011485:Protein Binding; D011506:Proteins / Q000276:immunology*; D013584:Sarcoma, Synovial / Q000276:immunology / Q000628:therapy; D022223:Vaccines, Subunit / Q000276:immunology* / Q000627:therapeutic use
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D011506:Proteins; D022223:Vaccines, Subunit