Immunogenicity of the carcinoembryonic antigen derived peptide 694 in HLA-A2 healthy donors and colorectal carcinoma patients

Autor: Hanifa Bouzourene, Gabriel Bricard, Jean Claude R Givel, Pedro M. S. Alves, Theres Fagerberg, Frédéric Lévy, Olivier Michielin, Henri Vuilleumier, Daniel E. Speiser, Sebastien Viatte, Pedro Romero, Thorsten Kruger, Jean Charles Cerottini
Rok vydání: 2007
Předmět:
Cancer Research
medicine.medical_treatment
Molecular Sequence Data
Immunology
Peptide
CD8-Positive T-Lymphocytes
Lymphocyte Activation
Major histocompatibility complex
Cancer Vaccines
Carcinoembryonic antigen
Cancer immunotherapy
Cell Line
Tumor
HLA-A2 Antigen
Amino Acid Sequence
Antigen Presentation/immunology
CD8-Positive T-Lymphocytes/cytology
CD8-Positive T-Lymphocytes/immunology
Cancer Vaccines/therapeutic use
Carcinoembryonic Antigen/genetics
Carcinoembryonic Antigen/immunology
Carcinoma/therapy
Cell Proliferation
Colorectal Neoplasms/immunology
Colorectal Neoplasms/therapy
HLA-A2 Antigen/metabolism
Humans
Leukocytes
Mononuclear/immunology
Peptide Fragments/genetics
Peptide Fragments/metabolism
Protein Binding
medicine
Immunology and Allergy
Avidity
chemistry.chemical_classification
Antigen Presentation
biology
business.industry
Immunogenicity
Carcinoma
Cancer
medicine.disease
Peptide Fragments
digestive system diseases
Carcinoembryonic Antigen
CTL
Oncology
chemistry
Leukocytes
Mononuclear
biology.protein
Colorectal Neoplasms
business
Zdroj: Cancer immunology, immunotherapy, vol. 56, no. 11, pp. 1795-1805
ISSN: 1432-0851
0340-7004
DOI: 10.1007/s00262-007-0323-2
Popis: Carcinoembryonic antigen (CEACAM5) is commonly overexpressed in human colon cancer. Several antigenic peptides recognized by cytolytic CD8+ T-cells have been identified and used in colon cancer phase-I vaccination clinical trials. The HLA-A*0201-binding CEA(694-702) peptide was recently isolated from acid eluted MHC-I associated peptides from a human colon tumor cell line. However, the immunogenicity of this peptide in humans remains unknown. We found that the peptide CEA(694-702) binds weakly to HLA-A*0201 molecules and is ineffective at inducing specific CD8+ T-cell responses in healthy donors. Immunogenic-altered peptide ligands with increased affinity for HLA-A*0201 were identified. Importantly, the elicited cytolytic T lymphocyte (CTL) lines and clones cross-reacted with the wild-type CEA(694-702) peptide. Tumor cells expressing CEA were recognized in a peptide and HLA-A*0201 restricted fashion, but high-CEA expression levels appear to be required for CTL recognition. Finally, CEA-specific T-cell precursors could be readily expanded by in vitro stimulation of peripheral blood mononuclear cell (PBMC) from colon cancer patients with altered CEA peptide. However, the CEA-specific CD8+ T-cell clones derived from cancer patients revealed low-functional avidity and impaired tumor-cell recognition. Together, using T-cells to demonstrate the processing and presentation of the peptide CEA694-702, we were able to corroborate its presentation by tumor cells. However, the low avidity of the specific CTLs generated from cancer patients as well as the high-antigen expression levels required for CTL recognition pose serious concerns for the use of CEA694-702 in cancer immunotherapy.
Databáze: OpenAIRE
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