LAUSR

Simple Summary Pre-clinical models are required to develop new therapeutics to improve patient care. In the prostate cancer field, significant progress has been made in the development of in vivo models but with a predominant focus on transgenics, which are time and cost prohibitive. Conversely, other available models do not closely resemble patient disease and tumour immune microenvironment. In this study, a new graft-based model is described, using a cell-line derived from a transgenic: the DVL3 model. Grafts using the DVL3 cells retain the pathological and immunological features of localized clinical disease, whilst genetically the model is sustained by poor prognosis drivers of disease progression. Irradiating tumours post-engraftment leads to remodeling of the tumour immune microenvironment and increased expression of genes associated with nucleic acid sensing pathways and the type I interferon response. This paper establishes this model as resource for the pre-clinical characterization of new prostate cancer therapies and biological responses to treatment. Abstract The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten−/−/trp53−/− mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents.