Several strategies that increase proteasomal degradation of antigen have been shown to improve MHC class I presentation of antigen. Because recent studies have demonstrated that the centrosome is a subcellular compartment rich in proteasomes, we hypothesized that targeting a tumor antigen to centrosomal compartments would enhance both the MHC class I presentation of antigen and the vaccine potency. We, therefore, created a chimera of γ-tubulin, an established centrosomal marker, with a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, in a DNA vaccine. The linkage of γ-tubulin to E7-targeted antigen to centrosomal compartments, resulted in enhanced MHC class I presentation of E7, and led to a marked increase in the number of E7-specific CD8+ T-cell precursors as well as a potent CD4-independent antitumor effect against an E7-expressing tumor cell line, TC-1. In addition, vaccination with γ-tubulin/E7 DNA in transporter associated with antigen presentation (TAP)-1-knockout mice revealed that the enhancement of E7-specific CD8+ T-cell immune responses is TAP-1-dependent. Our data suggest that the centrosome may be an important locus for MHC class I antigen processing and that targeting antigen to the centrosome can improve DNA vaccine potency.
|Original language||English (US)|
|Number of pages||6|
|State||Published - May 15 2003|
ASJC Scopus subject areas
- Cancer Research