Activation of Immune System Function Against Cancer by Heat Shock Proteins

Abstract

Chaperone proteins such as heat-shock proteins 70, 90 and 110, glucose-related protein 94 and calreticulin have been reported to be effective anti-tumor vaccines when purified from a tumor source. We have developed a procedure utilizing a free-solution-isoelectric focusing technique to obtain vaccines from tumor or normal tissue sources that are rich in multiple immunogenic chaperone proteins, called Chaperone-Rich Cell Lysate (CRCL). Tumor-associated peptides are presumed to be the currency of T-cell mediated anti-cancer immunity, and tumor-derived chaperone vaccines are believed to be purveyors of such peptides. As a novel anti-cancer strategy, we have examined the extent to which the peptide repertoire of CRCL can be manipulated. Here, we explored the concept of creating a designer CRCL, utilizing the adjuvant properties and the carrying capacity of CRCL to deliver exogenous antigenic peptides for DC-based presentation and ultimately demonstrate the anti-tumor efficacy of the designer vaccine in vivo. Designer CRCL allows for the development of personalized vaccines to those afflicted with cancer expressing known antigens.Growing evidence indicates that the stress response, specifically involving HSPs, has a profound impact on tumor immunogenicity. Enhancement of T-cell-mediated immunogenicity correlates with the expression of inducible heat shock protein 70 (iHSP70), the major heat-inducible member of the HSP70 family. In addition, studies have shown tumor-specific cell surface localization of iHSP70 correlates with an increased sensitivity to lysis mediated by human natural killer (NK) cells. Given these findings, investigating novel and effective means of modulating the heat shock response within tumor cells may bear great therapeutic potential and result in potent anti-tumor immune activity. Withaferin A (WA) is a compound isolated from the plant Withania somnifera that has been shown to induce a robust transcriptional heat shock response. In our studies, we found that WA treatment resulted in increased surface expression of iHSP70 in several tumor types leading to significant immunostimulatory effects. These findings indicated that WA-dependent modulation of the heat shock response may enhance tumor immunogenicity. Given the potent immunomodulatory and anti-tumor effects of WA as well as the adjuvanticity and specificity of peptide-complexed CRCL against tumors, these therapies individually have shown profound anti-cancer activity.