Optimization of a self antigen for presentation of multiple epitopes in cancer immunity
José A. Guevara-Patiño, … , Jedd D. Wolchok, Alan N. Houghton
José A. Guevara-Patiño, … , Jedd D. Wolchok, Alan N. Houghton
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1382-1390. https://doi.org/10.1172/JCI25591.
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Research Article Oncology

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.

Authors

José A. Guevara-Patiño, Manuel E. Engelhorn, Mary Jo Turk, Cailian Liu, Fei Duan, Gabrielle Rizzuto, Adam D. Cohen, Taha Merghoub, Jedd D. Wolchok, Alan N. Houghton

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Figure 5

Immunization with Tyrp1ee, exo-Tyrp1ee, and Tyrp1ee/ng protects mice from tumor challenge through a mechanism dependent on CD8+ T cells.

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Immunization with Tyrp1ee, exo-Tyrp1ee, and Tyrp1ee/n...
C57BL/6 mice (15 per group) were immunized once weekly for 4 weeks with different Tyrp1 constructs. Five days after the last vaccination, mice were challenged intradermally with 105 B16 melanoma cells. CD8+, CD4+, and NK cells were depleted by weekly intraperitoneal injection of 500 μg anti-CD8 (53.6-72), anti-CD4 (GK1.5), or anti-NK (PK-136) administered 3 days before starting immunization. Depleting antibodies were subsequently administrated every week for the duration of the experiment. Rat monoclonal IgG was administered as a control. Kaplan-Meier analyses are shown. (A) Immunization with Tyrp1ee DNA protected ~45% of mice challenged with B16 melanoma (P < 0.01) compared with mice vaccinated with the control (empty vector). Tumor protection was completely abrogated in mice depleted of CD8+ T cells, but neither CD4 nor NK cell depletion significantly affected tumor protection induced by immunization with Tyrp1ee. (B) Immunization with exo-Tyrp1ee DNA protected ~80% of mice (P < 0.05) compared with empty vector and was completely abrogated in mice depleted of CD8+ T cells. No significant decreases in tumor protection were observed in mice vaccinated with exo-Tyrp1ee and depleted of CD4 and NK cells. (C) Immunization with Tyrp1ee/ng conferred increased tumor protection (~70%) (P < 0.05 compared with empty vector or Tyrp1), which was completely dependent of CD8+ T cells.