Project Summary/Abstract: Prostate cancer (PCa) is particularly important in elderly men because of the high incidence and prevalence of disease and mortality in this group of patients. Although the case-fatality rate of PCa is quite low, deaths occur disproportionately in the elderly. However, the reasons for the increased incidence and mortality due to PCa in elderly men are not entirely clear. Low-grade inflammation (i.e., inflammaging) plays an important role in the aging process, and chronic inflammation contributes to the onset and progression of PCa. Inflammaging is often attributed to the progressive activation of immune cells. In that regard, a disruption in the balance of pro-inflammatory Th17 cells and homeostatic regulatory T (Treg) cells in favor of Th17 cells was reported previously to occur in non-cancer-related aging in humans and mice. Preliminary data support that elderly human prostate tissue had increased Th17/Treg ratio and the similar phenomenon was found in aged mice circulation and prostate tissue, and CD4+ T cell secreted factors from aged mice compared to young mice promote PCa cell proliferation, migration, and invasion. The long-term goal is to contribute toward the development of novel clinically useful strategies to treat or prevent PCa associated with advanced aging. The overall objective in this proposal is to determine how age-related Th17/Treg imbalance contributes to prostate carcinogenesis. The central hypothesis is that age-related disruption of Th17/Treg axis promotes PCa initiation and progression. The rationale for the proposed research is that a determination of how Th17/Treg imbalance promotes prostate carcinogenesis is likely to provide new opportunities for the subsequent development of targeted therapeutics to the prevention/treatment of prostate cancers associated with advanced aging. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify associations between Th17/Treg ratio alteration and progression of human PCa associated with advanced aging. 2) Define how aging-associated imbalances in Th17/Treg axis drive PCa. 3) Determine the efficacy of therapeutic targeting of Th17/Treg axis in preventing aging-associated PCa. In aim 1, the expression of Th17/Treg and NF-kB will be examined in human normal and PCa specimens at different ages. In aim 2, the Batf and Pten (tumor suppressor gene) double knockout mouse model generated at different ages will be used to assess whether Batf status and age plays a critical role in PCa initiation and progression. In aim 3, the anti- IL-23p19 antibody and small molecule SR1555 (both suppress Th17/stimulate Treg function) will be tested. The approach is innovative, in the applicant’s opinion, because the tumor growth can be compared in the same time interval post-Pten excision between the aged and non-aged mice. The proposed research is significant, as the concept is novel and has clinical significance because rectifying Th17/Treg imbalance has the potential to be developed into prognostic indicator of PCa and therapeutics in the prevention and treatment of PCa in the elderly.

Project Narrative The proposed research is relevant to public health because the discovery of how aging-related Th17/Treg imbalance promotes PCa is ultimately expected to help inform the identification of new targeted therapeutic interventions against aging-associated prostate cancer. The findings from this project will have significant potential to be developed into prognostic biomarkers and/or translated into the prevention and treatment of human prostate cancer in the elderly. The proposed research is relevant to the part of the NIH mission pertaining to research involving host predisposing states that investigates the role of comorbidity such as aging as an etiological factor in cancer.