Investigating the Role of PTEN in Prostate Cancer Cell-Intrinsic Type I Interferon Responses
Prostate cancer (PCa) is the most commonly diagnosed cancer in Canadian men and is characterized by a dysregulated immune response which is influenced by cancer cell-intrinsic genetic aberrations. Loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) occurs in 20-30% of PCa tumors and is associated with disease progression and an aggressive phenotype. Clinical and preclinical studies demonstrate that loss of PTEN expression correlates with decreased Type I Interferon (IFN1) pathway markers, suggesting that PTEN has a role in regulating the immune response by impacting IFN1 signaling. To characterize the role of PTEN in shaping cellular immune-related properties, we assessed cell-intrinsic IFN1 responses using NanoString gene expression analysis and secreted cytokine profiling in PCa cells with variable PTEN expression. We observed distinct response patterns at baseline and following treatment with IFN1 agonists. We generated PTEN knockout derivatives of PCa cells and observed statistically significant differences in expression patterns of IFN1 pathway genes in PTEN-deficient cells during normal growth and following treatment with IFN1 agonists. Genes involved in innate immune signaling, antiviral responses, and inflammation were significantly decreased in PTEN-knockout cells. Additionally, PTEN-knockout cells had significantly decreased secreted levels of major inflammatory and chemotactic cytokines including CXCL1 and CXCL10 compared to PTEN-intact PCa cells. Given the significance of the cross-talk between cancer cells and surrounding immune cells in cancer progression, these findings are important in elucidating the specific contribution of cell-intrinsic pathways to the PCa tumor microenvironment. This investigation may lead to exploitation of PCa cell-intrinsic IFN1 pathways for rational design and use of immune-based therapies to improve management of PCa.
URI for this recordhttp://hdl.handle.net/1974/24312
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