Tumor immunity in prostate cancer (PCa): Novel treatment approaches based on CD40-CD40L interactions

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Prostate cancer (PCa) is one of the most threatening cancers in men, diagnosed in one of six men during their lifetimes. Conventional therapies often only induce transient therapeutic effects, particularly in the case of hormone independent PCa. There is an urgent need to develop novel efficient PCa treatment approaches and novel biomarkers. Consequently, in this joint grant application we aim to develop novel treatment strategies targeting low immunogenic PCa based on the novel antigen ZP3, expressed on PCa and on triggering the immunopotentiating CD40/CD40L signal axis. In respect of the complex dynamic interplay between tumor-stroma and immune cells, the various functional different CD40/CD40L interactions, and the sensitivity of PCa to a chronic inflammatory microenvironment a multi-disciplinary research team is established to investigate following aspects in tumor immunology:I. Impact of CD40 ligation on tumor-stroma and immune cells provided by CD40L expressing CD8+ Helper T cellsII. Negative regulation of CD40/CD40L mediated T-cell activation by stromal fibroblasts, especially in the presence of sexual hormones or inflammatory cytokinesIII. Induction of tumor rejection based on targeting CD40/CD40L pathways and ZP3 interactions and establishment of ZP3 as a potential biomarker of PCaThe connected projects will reveal essential knowledge about the mechanisms how tumor-stroma is targeted efficiently by generated tumor-antigen specific immune responses and which factors influence these interactions. Together with these obtained results, the application and validation of the novel PCa-specific antigen ZP3 in all three subprojects may lead to the establishment of prognostic biomarkers and novel immunotherapy options for PCa.