The role of aging T-lymphocytes in prostate cancer development



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Age is the single greatest factor associated with increased risk for prostate cancer development. Evidence implicates progressive age-related immune dysfunction with increased prostate cancer incidence. The aged T cell response is characterized by increased production of pro-inflammatory cytokines, which could significantly contribute to prostate tumorigenesis through induction of key pro-survival factors. The objective of these studies was to determine how age-related changes in T-lymphocyte function contribute to prostate tumorigenesis. The hypothesis that age-related changes in T-lymphocyte function to a pro-inflammatory phenotype promote prostate cancer development was tested using the glycerol-3-phosphate acyltransferase-1 (GPAT-1) knock-out mouse, which mimics many of the characteristics of an aged immune system. T cells from old (24-month) mice and aging-mimic T cell GPAT-1 [superscript -/-] mice generate more pro-inflammatory cytokines than T-lymphocytes from wild type mice. These cytokines turn on inflammatory pathways that stimulate proliferation, tissue disruption, and tumor growth. Initial studies showed that secreted factors from aging and T cell aging mimic GPAT-1 [superscript -/-] mice produce circulating factors that induce pro-inflammatory pathways in prostate cells, most notably the nuclear factor kappa-light-chain-enhancer of activated B cells (NF- [subscript K] B). Additionally, results from recent experiments demonstrate that serum from the GPAT-1 [superscript -/-] mice induce protein expression of downstream targets of NF- [subscript K] B in the prostate, most notably factors that induce macrophage infiltration and key pro-survival proteins. Furthermore, my experimental results suggest that the increased production of interleukin 17 (IL-17) by aged T cells play a role in the induction of proinflammatory pathways in the prostate. Based on these findings additional studies were design to determine if the increased production of pro-inflammatory cytokines by aging T-lymphocytes contributes to a more malignant phenotype in the prostate. Finally, the inter-relationship between an aging immune system and the aging tissues in the body was explored. Findings from these studies provide evidence that the dysregulation of cytokine production seen in aged T cells may directly contribute to the increased risk for prostate cancer in the elderly. This new perspective regarding the role of the aging immune system in cancer development opens new avenues for development of potential preventive interventions and screening biomarkers.