CD8(+) T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients.
NY-ESO-1 is a germ cell antigen aberrantly expressed in different tumor types that elicits strong humoral and cellular immune responses in cancer patients. Monitoring spontaneous CD8(+) T cell responses against NY-ESO-1 peptides 157-165 (S9C) and 157-167 (S11L) in a series of HLA-A2(+) cancer patients showed that these two peptides had overlapping antigenic profiles and were equally immunogenic. However, discrepancies between S9C and S11L reactivities were observed upon vaccination with both peptides to generate or boost T cell responses to NY-ESO-1 in cancer patients. We here analyze the fine specificity of these responses and describe an HLA-A2-restricted epitope, NY-ESO-1 peptide 159-167 (L9L), which is strongly recognized by CD8(+) T cells as a result of peptide vaccination of cancer patients. Responses to L9L were stimulated by S11L and appeared early in the course of vaccination, independently of S9C responses. However, L9L-specific CD8(+) T cells failed to recognize tumor cells naturally expressing NY-ESO-1 or B lymphoblastoid cells transduced with NY-ESO-1. Processing of L9L could be rescued after IFN-gamma treatment of tumor cells or by dendritic cells pulsed with NY-ESO-1 protein/antibody immune complexes. The present results demonstrate a dual specificity within peptide S11L, with S9C as the natural antigenic tumor epitope, and L9L as a cryptic epitope with dominant immunogenicity upon vaccination that diverts the immune response from tumor recognition. These unanticipated findings raise questions about the use of S11L in the clinic and emphasize the importance of analyzing the fine specificity of vaccine-induced T cell responses in patients as a basis for constructing effective cancer vaccines.
Gnjatic
Sacha
S
Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. gnjatics@mskcc.org
Jäger
Elke
E
Chen
Weisan
W
Altorki
Nasser K
NK
Matsuo
Mitsutoshi
M
Lee
Sang-Yull
SY
Chen
Qiyuan
Q
Nagata
Yasuhiro
Y
Atanackovic
Djordje
D
Chen
Yao-Tseng
YT
Ritter
Gerd
G
Cebon
Jonathan
J
Knuth
Alexander
A
Old
Lloyd J
LJ
D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D003429:Cross Reactions; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008565:Membrane Proteins; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011506:Proteins / Q000008:administration & dosage* / Q000276:immunology
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D011506:Proteins