Identification and enhancement of HLA-A2.1-restricted CTL epitopes in a new human cancer antigen-POTE

Identification of CD8(+) T cell epitopes that can induce T cells to kill tumor cells is a fundamental step for development of a peptide cancer vaccine. POTE protein is a newly identified cancer antigen that was found to be expressed in a wide variety of human cancers, including prostate, colon, lung...

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Bibliographic Details
Published in:PloS one 2013-06, Vol.8 (6), p.e64365-e64365
Main Authors: Huang, Yi-Hsiang, Terabe, Masaki, Pendleton, C David, Stewart Khursigara, Deborah, Bera, Tapan K, Pastan, Ira, Berzofsky, Jay A
Format: Article
Language:English
Subjects:
Affinity
Amino Acid Sequence
Amino acids
Animals
Antigenic determinants
Antigens
Antigens, Neoplasm - chemistry
Antigens, Neoplasm - immunology
Binding
Biology
Cancer
Cancer therapies
Cancer vaccines
CD8 antigen
Cell Line, Tumor
Colon
Cross Reactions
Cytotoxicity
Development and progression
Epitopes
Epitopes, T-Lymphocyte - immunology
Hepatitis
Histocompatibility antigen HLA
HIV
HLA antigens
HLA-A2 Antigen - immunology
Human immunodeficiency virus
Humans
Immunogenicity
Immunological tolerance
Immunotherapy
Laboratories
Ligands
Lung cancer
Lung diseases
Lymphocytes
Lymphocytes T
Medical research
Medicine
Metastasis
Mice
Mice, Transgenic
Molecular biology
Non-small cell lung cancer
Non-small cell lung carcinoma
Pancreas
Peptides
Phenylalanine
Placenta
Prostate
Prostate cancer
Protein Structure, Tertiary
Receptors, Antigen, T-Cell - metabolism
T cells
T-Lymphocytes, Cytotoxic - immunology
Transgenic animals
Tumor cells
Tumors
Tyrosine
Vaccines
Valine
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Summary:Identification of CD8(+) T cell epitopes that can induce T cells to kill tumor cells is a fundamental step for development of a peptide cancer vaccine. POTE protein is a newly identified cancer antigen that was found to be expressed in a wide variety of human cancers, including prostate, colon, lung, breast, ovary and pancreas. Here, we determined HLA-A2.1-restricted cytotoxic T lymphocyte (CTL) epitopes in the POTE protein, and also designed enhanced epitopes by amino acid (AA) substitutions. Five 9-mer peptides were first selected and their binding affinity to HLA-A2 molecules was measured by the T2 binding assay. POTE 272-280 and POTE 323-331 showed the strongest HLA-A2 binding affinity. AA substituted peptides POTE 252-9V (with valine at position 9), POTE 553-1Y (with tyrosine at position 1) and POTE 323-3F (with phenylalanine at position 3) conferred higher affinity for HLA-A2, and induced CTL responses cross-reactive with wild type antigens. While POTE 252-9V was the strongest in this respect, POTE 323-3F had the greatest increase in immunogenicity compared to wild type. Importantly, two modified epitopes (POTE-553-1Y and POTE-323-3F) induced CTLs that killed NCI-H522, a POTE-expressing HLA-A2(+) human non-small cell lung cancer cell line, indicating natural endogenous processing of these epitopes. In conclusion, the immunogenicity of POTE epitopes can be enhanced by peptide modification to induce T cells that kill human cancer cells. A combination of POTE 553-1Y and POTE 323-3F epitopes might be an attractive vaccine strategy for HLA-A2 cancer patients to overcome tolerance induced by tumors and prevent escape.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0064365