CD8+ T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients

被引:77
作者
Gnjatic, S
Jäger, E
Chen, WS
Altorki, NK
Matsuo, M
Lee, SY
Chen, QY
Nagata, Y
Atanackovic, D
Chen, YT
Ritter, G
Cebon, J
Knuth, A
Old, LJ
机构
[1] Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York Branch, New York, NY 10021 USA
[2] Krankenhaus NW Frankfurt, Med Klin 2, D-60488 Frankfurt, Germany
[3] Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, Melbourne Branch, Melbourne, Vic 3084, Australia
[4] Cornell Univ, Weill Med Coll, Dept Cardiothorac Surg, New York, NY 10021 USA
[5] Cornell Univ, Weill Med Coll, Dept Pathol, New York, NY 10021 USA
关键词
D O I
10.1073/pnas.142417699
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:11813 / 11818
页数:6
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