Optimization of a self antigen for presentation of multiple epitopes in cancer immunity.

The Journal of Clinical Investigation
José A Guevara-PatiñoAlan N Houghton

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 multi-specific 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 demo...Continue Reading

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Citations

Jul 31, 2012·Current Oncology Reports·M Lia Palomba
Oct 27, 2012·Journal of Medicinal Chemistry·Amanda Shanks HuynhJosef Vagner
Feb 28, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Manuel E EngelhornJedd D Wolchok
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Methods Mentioned

BETA
glycosylation
protein folding
flow cytometry
PCR
fluorescence-activated cell sorting
transfection

Software Mentioned

KS
Lysis II

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