RESUMO
Heat shock cognate protein 70 (HSC70), a highly conserved protein and a member of the family of molecular chaperones, has the ability to induce cytotoxic T lymphocyte (CTL) responses through binding and carrying antigenic peptides. We demonstrated in this study that the HSC70 gene encodes two antigenic peptides recognised by HLA-B46-restricted and tumour-reactive CTLs established from tumour-infiltrating lymphocytes of a colon cancer. These HSC70-derived peptides, at amino-acid positions 106-114 and 233-241, had the ability to induce HLA-B46-restricted and peptide-specific CTLs, which are reactive to tumour cells, from peripheral blood mononuclear cells of the majority of epithelial cancer patients tested. These results, along with those from the previous studies, indicate the two ways of HSC70 involvement in the immune responses to tumours: chaperones and antigens, and thus may provide a new insight for the development of HSC70-directed cancer-specific immunotherapy.
Assuntos
Antígenos de Neoplasias/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-B/imunologia , Proteínas de Choque Térmico HSP70/genética , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos CD , Células COS , Chlorocebus aethiops , Citotoxicidade Imunológica/imunologia , DNA Complementar , Proteínas de Choque Térmico HSC70 , Humanos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral , Neoplasias/genética , Ligação Proteica/imunologia , Transfecção , Células Tumorais CultivadasRESUMO
Recent identification of cytotoxic T lymphocyte (CTL)-directed peptides binding to the HLA-A2 and -A24 alleles has opened the door to peptide-based cancer immunotherapies. However, subsequent studies have succeeded in identifying no more than a few CTL-directed peptides that bind to alleles other than HLA-A2 and -A24, thus hampering development of immunotherapies directed at other alleles. We have shown in this study that two genes coding for ribosomal proteins (S2 and L10a) encoded tumor antigens recognized by HLA-A26-restricted CTLs. The S2 mRNA was expressed in all of the cancer cells and non-malignant cell lines tested, but was not expressed in normal tissues except for the testis, muscle, and peripheral mononuclear leukocyte cell (PBMC). In contrast, the L10a mRNA was expressed in all of these cancer and non-malignant cell lines, and also normal tissues, although the expression levels in normal tissues were mostly low. One S2-derived peptide and two L10a-derived peptides had the ability to induce HLA-A26-restricted and peptide-specific CTLs reactive to tumor cells in PBMCs of cancer patients, respectively. These ribosomal protein-derived peptides, and particularly the S2-derived peptide, could be suitable for use in peptide-based immunotherapy for HLA-A26+ cancer patients.
