Optimization of a self antigen for presentation of multiple epitopes in cancer immunity Journal Article
| Authors: | Guevara-Patiño, J. A.; Engelhorn, M. E.; Turk, M. J.; Liu, C.; Duan, F.; Rizzuto, G.; Cohen, A. D.; Merghoub, T.; Wolchok, J. D.; Houghton, A. N. |
| Article Title: | Optimization of a self antigen for presentation of multiple epitopes in cancer immunity |
| Abstract: | T cells recognizing self antigens expressed by cancer cells are prevalent in the immune repertoire. However, activation of these autoreactive T cells is limited by weak signals that are incapable of fully priming naive T cells, creating a state of tolerance or ignorance. Even if T cell activation occurs, immunity can be further restricted by a dominant response directed at only a single epitope. Enhanced antigen presentation of multiple epitopes was investigated as a strategy to overcome these barriers. Specific point mutations that create altered peptide ligands were introduced into the gene encoding a nonimmunogenic tissue self antigen expressed by melanoma, tyrosinase-related protein-1 (Tyrp1). Deficient asparagine-linked glycosylation, which was caused by additional mutations, produced altered protein trafficking and fate that increased antigen processing. Immunization of mice with mutated Tyrp1 DNA elicited cross-reactive CD8+ T cell responses against multiple nonmutated epitopes of syngeneic Tyrp1 and against melanoma cells. These multispecific anti-Tyrp1 CD8+ T cell responses led to rejection of poorly immunogenic melanoma and prolonged survival when immunization was started after tumor challenge. These studies demonstrate how rationally designed DNA vaccines directed against self antigens for enhanced antigen processing and presentation reveal novel self epitopes and elicit multispecific T cell responses to nonimmunogenic, nonmutated self antigens, enhancing immunity against cancer self antigens. |
| Keywords: | survival; nonhuman; neoplasms; antigen expression; cd8+ t lymphocyte; cd8-positive t-lymphocytes; t-lymphocytes; mouse; animals; mice; melanoma; models, biological; animal experiment; animal model; drug effect; mutational analysis; mice, inbred c57bl; antigen presentation; dna; immune response; immunogenicity; epitope; glycosylation; autoantigens; tumor immunity; autoimmunity; dna vaccine; point mutation; cross reaction; antigen binding; hla a antigen; tyrosinase related protein 1; oxidoreductases; t lymphocyte activation; asparagine; major histocompatibility antigen class 1; immunization; epitopes |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 116 |
| Issue: | 5 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2006-05-01 |
| Start Page: | 1382 |
| End Page: | 1390 |
| Language: | English |
| DOI: | 10.1172/jci25591 |
| PUBMED: | 16614758 |
| PROVIDER: | scopus |
| PMCID: | PMC1435720 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 41" - "Export Date: 4 June 2012" - "CODEN: JCINA" - "Source: Scopus" |
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