Background
Prostate cancer (PCa) is highly prevalent. Of patients with advanced metastatic disease, 80-90% will have bone metastases that are morbid and almost always incurable. While the mechanisms that induce the outgrowth of disseminated tumour cells in bone remain incompletely understood, emerging evidence has revealed that evading immune surveillance is a critical factor in bone metastasis formation. Our laboratory has established a link between poor immunogenicity of bone metastases and the loss of type I interferon (IFN) cytokine signalling - a pathway essential to the induction of innate and adaptive immunity.
Aim
We aim to purify bone metastases from immunocompetent mouse models and develop a drug screening method to uncover epigenetic drugs and novel gene targets that restore IFN signalling and enhance anti-tumour immunity in PCa bone metastases.
Methods
We have derived mouse metastatic lines from the RM-1 syngeneic C57 BL/6 model. Using an IFN-stimulated response element (ISRE) reporter system, along with high throughout FACS-based detection of MHC I and PDL-1, we have developed a 384-well platform for screening for novel treatments and combination approaches that activate IFN pathway and increase MHC I and PDL-1.
Results
Bone derived RM-1 cells displayed reduced IFN signalling and MHC I expression compared to the parental line. Transduction of RM-1 cells with a GFP-based ISRE reporter allowed the development of a sensitive platform for detecting changes to ISRE signalling, along with MHC I and PD-L1 expression. This system has proven to be useful in testing combination treatment approaches that enhance IFN signalling and immunogenicity. Whilst bone metastatic cells lack the ability to respond to the toll-like receptor 3 (TLR3) agonist poly I:C due to a deficient signalling pathway, combination with epigenetic drugs can activate IFN pathway and increase immunogenicity. We have performed a high-throughput epigenetic drug screening (700 compounds) in bone-derived RM-1 cells to identify candidate epigenetic compounds that can induce IFN pathway.
Conclusion
This high-throughput drug screening has the potential to identify drugs that can enhance tumour cell vulnerability to immune-based therapies. This study will lead to preclinical testing of lead epigenetic drugs that may lead to personalized treatment strategies for bone metastasis.