Guadecitabine-directed immune regulation in targeting prostate cancer

Project Summary Immunotherapy has transformed the treatment landscape for many cancers, but its clinical benefit is only marginal in prostate cancer patients. Epigenetic changes and altered immune signaling pathways can downregulate antigen presentation, resulting in resistance to immunotherapies. There is a significant interest in targeting cancer cells via reversing epigenetic mechanisms to modify the host intrinsic immunity. Epigenetic therapy has the ability to activate tumor-suppressing programs and modulate the tumor microenvironment (TME) by augmenting immune cell infiltration. In this study, we used a hypomethylating agent, guadecitabine (gDEC), and demonstrated that gDEC leads to the upregulation of epigenetic activating enzymes contributing to the overall prostate cancer phenotype change and anticancer effect independent of apoptosis. We also observed that gDEC induces the level of Class I MHC molecules on the surface of prostate cancer cells, making the cancer cells vulnerable to immune cell targets. Based on our strong preliminary data, we proposed to test a novel hypothesis that gDEC augments the process of antigen presentation, compelling prostate cancer cells susceptible to CD8+ T cells induced by immunotherapy. The rationale for this hypothesis is that gDEC increases the process of antigen presentation with the potential to provoke neoantigens, making the tumor cells immunogenic and vulnerable to immune targets. Furthermore, the combined use of an adenovirus-based vaccine expressing prostate cancer-specific antigens (Ad-PS2 bivalent vaccine) induces CD8+ T cell infiltration and eliminates the established tumors. Therefore, we aimed to determine the crosstalk mechanisms between the tumor and immune cells in the prostate TME following epigenetic remodeling and develop a novel immunotherapy regimen inducing long-lasting, antigen-specific antitumor immunity targeting prostate cancer.