A Modified Tyrosinase-Related Protein 2 Epitope Generates High-Affinity Tumor-Specific T Cells but Does Not Mediate Therapeutic Efficacy in an Intradermal Tumor Model
| Autor: | Steven W. Dow, Ross M. Kedl, Sean M. McGurran, Jill E. Slansky, Jennifer A. McWilliams |
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| Rok vydání: | 2006 |
| Předmět: |
Skin Neoplasms
Injections Intradermal T cell Immunology Melanoma Experimental Epitopes T-Lymphocyte Streptamer Biology Lymphocyte Activation Cancer Vaccines Epitope Mice Antigens Neoplasm T-Lymphocyte Subsets Cell Line Tumor Cell Adhesion medicine Animals Immunology and Allergy Cytotoxic T cell H-2 Antigens Molecular biology Intramolecular Oxidoreductases Mice Inbred C57BL medicine.anatomical_structure Immunization Female Tyrosinase-related protein-2 Peptides Neoplasm Transplantation Intracellular CD8 Protein Binding |
| Zdroj: | The Journal of Immunology. 177:155-161 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The generation of tumor-specific T cells is hampered by the presentation of poorly immunogenic tumor-specific epitopes by the tumor. Here, we demonstrate that, although CD8+ T cells specific for the self/tumor Ag tyrosinase-related protein 2 (TRP2) are readily detected in tumor-bearing hosts, vaccination of either tumor-bearing or naive mice with an epitope derived from TRP2 fails to generate significant numbers of tetramer-staining TRP2-specific T cells or antitumor immunity. We identified an altered peptide epitope, called deltaV, which elicits T cell responses that are cross-reactive to the wild-type TRP2 epitope. Immunization with deltaV generates T cells with increased affinity for TRP2 compared with immunization with the wild-type TRP2 epitope, although TRP2 immunization often generates a greater number of TRP2-specific T cells based on intracellular IFN-γ analysis. Despite generating higher affinity responses, deltaV immunization alone fails to provide any greater therapeutic efficacy against tumor growth than TRP2 immunization. This lack of tumor protection is most likely a result of both the deletion of high affinity and functional tolerance induction of lower affinity TRP2-specific T cells. Our data contribute to a growing literature demonstrating the ability of variant peptide epitopes to generate higher affinity T cell responses against tumor-specific Ags. However, consistent with most clinical data, simple generation of higher affinity T cells is insufficient to mediate tumor immunity. |
| Databáze: | OpenAIRE |
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