Abstract
The proteasome is a cellular subunit that degrades intracellular proteins into small pieces called peptides. Degradation of proteins into peptides occurs through one of two types of proteasomes: constitutive proteasome (cPr) and immunoproteasome (iPr), each giving rise to a unique repertoire of peptides. Most cells, including tumor cells, express the cPr, while dendritic cells (DCs), the master T cell educators of the immune system, constitutively express the iPr. Presentation of peptides processed through the iPr in DCs may activate T cells that cannot recognize peptides processed through the cPr in tumor cells, leading to a non-functional antitumor immune response. To eliminate this problem, we have investigated the use of two drugs discovered by Onyx Pharmaceuticals that selectively inhibit either the c20S of the cPr or the i20S of the iPr in tumor cells and DCs respectively. The drug ONX 0914 inhibits iPr activity. We have determined that the ONX 0914 concentration of 250nM is optimal to block iPr function and maximize DC viability. Using ONX 0914 we have demonstrated that the major histocompatibility complex I (MHC I) Kb-restricted epitope, gp-10025-33, is processed through the iPr. The drug PR-825 inhibits cPr activity. Using PR-825, we have determined that the peptide OVA257-264 is processed through the cPr. We are using these drugs to optimize DC-based vaccines in a murine model of melanoma.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A61.
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