Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide.

Details

Serval ID
serval:BIB_D59B0D3DD07F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide.
Journal
Cancer immunology, immunotherapy
Author(s)
Iero M., Squarcina P., Romero P., Guillaume P., Scarselli E., Cerino R., Carrabba M., Toutirais O., Parmiani G., Rivoltini L.
ISSN
0340-7004
Publication state
Published
Issued date
2007
Peer-reviewed
Oui
Volume
56
Number
12
Pages
1979-1991
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The use of "altered peptide ligands" (APL), epitopes designed for exerting increased immunogenicity as compared with native determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly promotes the generation of low-affinity CD8(+) T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained by priming peripheral blood mononuclear cells from HLA-A*0201(+) healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- gamma release CEA(+)CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any clinical usage of APL as anti-cancer vaccines.
Keywords
Antibody Affinity, Antigens, Neoplasm/chemistry, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Cancer Vaccines, Colorectal Neoplasms/metabolism, Epitopes/chemistry, HLA-A Antigens/chemistry, Immunotherapy/methods, Leukocytes, Mononuclear/metabolism, Ligands, Oligopeptides/chemistry, Peptides/chemistry, Receptors, Antigen, T-Cell/immunology, Risk, T-Lymphocytes/metabolism
Pubmed
Web of science
Create date
28/01/2008 11:28
Last modification date
20/08/2019 15:55
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