TY - JOUR
T1 - CD8+ T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients
AU - Gnjatic, Sacha
AU - Jäger, Elke
AU - Chen, Weisan
AU - Altorki, Nasser K.
AU - Matsuo, Mitsutoshi
AU - Lee, Sang Yull
AU - Chen, Qiyuan
AU - Nagata, Yasuhiro
AU - Atanackovic, Djordje
AU - Chen, Yao Tseng
AU - Ritter, Gerd
AU - Cebon, Jonathan
AU - Knuth, Alexander
AU - Old, Lloyd J.
PY - 2002/9/3
Y1 - 2002/9/3
N2 - 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 (59C) 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 511L 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-γ 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 511L, with 59C 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 511L 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.
AB - 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 (59C) 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 511L 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-γ 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 511L, with 59C 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 511L 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.
UR - http://www.scopus.com/inward/record.url?scp=18544373394&partnerID=8YFLogxK
U2 - 10.1073/pnas.142417699
DO - 10.1073/pnas.142417699
M3 - Article
C2 - 12186971
AN - SCOPUS:18544373394
SN - 0027-8424
VL - 99
SP - 11813
EP - 11818
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -