Dysregulation of IL-17 Production in Aged T-Lymphocytes Promotes Pro-tumorigenic Changes in Prostate Epithelial Cells

Abstract

Event Abstract Back to Event Dysregulation of IL-17 Production in Aged T-Lymphocytes Promotes Pro-tumorigenic Changes in Prostate Epithelial Cells Alejandra De Angulo1*, Robert Faris1, Christopher Jolly1 and Linda DeGraffenried1 1 University of Texas at Austin, United States Background: Prostate cancer represents 8% of all new cancer cases world-wide and is the second leading cause of cancer death in men. Incidence is closely associated with aging, but the mechanisms by which aging promotes prostate cancer development are unclear, limiting the development of effective preventive interventions. Aging is accompanied by immune dysfunction and a progressive increase in pro-inflammatory cytokines, including Interleukin 17 (IL-17). Aging-associated increases in circulating IL-17 promotes pro-inflammatory signaling in prostate epithelial cells, possibly contributing to tumorigenesis. Methods: Serum and splenic CD4+ T-lymphocytes from young T cell aging-mimic mice as well as young and aged wild-type mice were collected. Surface markers and intracellular levels of IL- 17, IFN-γ and IL-4 in isolated CD4+ T-cells were measured using flow-cytometry. shRNA was used to knock down the IL-17 receptor in LNCaP prostate cancer cells and RWPE-1 non-transformed prostate epithelial cells, which were then exposed to mouse sera or conditioned media from stimulated T-lymphocytes. NF-kB and STAT3 activation, NF-kB and STAT3 target gene expression, and epithelial cell transformation were all measured in prostate epithelial cells. Results: T cells from aging and aging-mimic mice secrete elevated levels of IL-17, possibly due to an imbalance in the TH17/TH1 and TH17/TH2 cell ratios. T-lymphocyte-secreted IL-17 from aging-mimic mice induced NF-kB and STAT3 activity and target gene expression in LNCaP and RWPE-1 cells. Importantly, IL-17 also promoted pro-tumorigenic changes in RWPE-1 cells, leading to a pre-transformed phenotype. Inhibition of IL-17 signaling blocked age-induced changes in both the cancer and non-transformed prostate epithelial cells. Conclusion: Aging of the immune system is associated with increased levels of IL-17, which stimulates the pro-inflammatory NF-kB and STAT3 pathways in prostate epithelial cells and activates programming associated with cellular transformation. Inhibition of IL-17 signaling blocks the pro-tumorigenic activity induced by aging T cells. These findings provide evidence that the dysregulation of IL-17 production in aged T-cells may directly contribute to the increased risk for prostate cancer. Future novel immunotherapies for prostate cancer prevention could target the increase production of IL-17 associated with aging