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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.
Cancer Immunol Immunother. 2007 Dec; 56(12):1979-91.CI

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.

Authors+Show Affiliations

Unit of Immunotherapy of Human Tumors, IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17564703

Citation

Iero, Manuela, et al. "Low TCR Avidity and Lack of Tumor Cell Recognition in CD8(+) T Cells Primed With the CEA-analogue CAP1-6D Peptide." Cancer Immunology, Immunotherapy : CII, vol. 56, no. 12, 2007, pp. 1979-91.
Iero M, Squarcina P, Romero P, et al. Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide. Cancer Immunol Immunother. 2007;56(12):1979-91.
Iero, M., Squarcina, P., Romero, P., Guillaume, P., Scarselli, E., Cerino, R., Carrabba, M., Toutirais, O., Parmiani, G., & Rivoltini, L. (2007). Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide. Cancer Immunology, Immunotherapy : CII, 56(12), 1979-91.
Iero M, et al. Low TCR Avidity and Lack of Tumor Cell Recognition in CD8(+) T Cells Primed With the CEA-analogue CAP1-6D Peptide. Cancer Immunol Immunother. 2007;56(12):1979-91. PubMed PMID: 17564703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide. AU - Iero,Manuela, AU - Squarcina,Paola, AU - Romero,Pedro, AU - Guillaume,Philippe, AU - Scarselli,Elisa, AU - Cerino,Raffaele, AU - Carrabba,Matteo, AU - Toutirais,Olivier, AU - Parmiani,Giorgio, AU - Rivoltini,Licia, Y1 - 2007/06/13/ PY - 2007/04/16/received PY - 2007/05/17/accepted PY - 2007/6/15/pubmed PY - 2007/12/6/medline PY - 2007/6/15/entrez SP - 1979 EP - 91 JF - Cancer immunology, immunotherapy : CII JO - Cancer Immunol. Immunother. VL - 56 IS - 12 N2 - 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. SN - 0340-7004 UR - https://www.unboundmedicine.com/medline/citation/17564703/Low_TCR_avidity_and_lack_of_tumor_cell_recognition_in_CD8_+__T_cells_primed_with_the_CEA_analogue_CAP1_6D_peptide_ L2 - https://dx.doi.org/10.1007/s00262-007-0342-z DB - PRIME DP - Unbound Medicine ER -