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01.12.2007 | Original Article

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

verfasst von: Manuela Iero, Paola Squarcina, Pedro Romero, Philippe Guillaume, Elisa Scarselli, Raffaele Cerino, Matteo Carrabba, Olivier Toutirais, Giorgio Parmiani, Licia Rivoltini

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 12/2007

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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- γ 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.

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Titel: Low TCR avidity and lack of tumor cell recognition in CD8+ T cells primed with the CEA-analogue CAP1-6D peptide
verfasst von: Manuela Iero
Paola Squarcina
Pedro Romero
Philippe Guillaume
Elisa Scarselli
Raffaele Cerino
Matteo Carrabba
Olivier Toutirais
Giorgio Parmiani
Licia Rivoltini
Publikationsdatum: 01.12.2007
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 12/2007
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-007-0342-z

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

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