Age-Related Elevated Th17 Immune Response Contributes To Prostate Carcinogenesis

Prostate cancer is associated with advanced age, but how age contributes to prostate cancer remains unknown. Aging is characterized by a chronic, low-grade systemic inflammation, so called “inflamm-aging”. Data supporting the role of inflammation in prostate cancer comes from a variety of fields, thus, inflamm-aging represents a strong candidate to connect age and prostate cancer. Recent studies have shown that T helper (Th) 17 immune responses are elevated in aging humans and mice. However, the contribution of age-related elevated Th17 immune responses to prostate cancer remains unclear. The aim of this study was to investigate the role of Th17 immune responses in the aging process in prostate carcinogenesis. Initial investigation of mouse prostate tissues from wild-type C57BL/6J mice showed that aged (u003e80-week-old) mouse prostates had significantly increased inflammatory cell infiltration, increased protein and mRNA levels of pro-inflammatory mediators and Th17 cytokines and activated NF-κB and ERK1/2 signaling compared to young (12-20-week-old) mouse prostates. To gain a mechanistic understanding of how the Th17 immune response promotes prostate carcinogenesis in the aging process, we isolated splenic T cells from young and aged mice. Naive CD4 + T cells isolated from the young and aged mice were differentiated in Th17 polarization conditions. Th0 cells were cultured in the absence of cytokines to serve as control. Four days later cells were re-stimulated with anti-CD3 and CD28 with PMA and ionomycin in the presence of brefeldin A for 6 hours, then the cells were washed and re-cultured in serum free media for 24 hours. Cells were then collected and used for flow cytometry or qPCR. Conditioned media from both young and aged Th0 and Th17 cultures were collected and used in subsequent experiments. Results indicated that Th17 cells, Th17 cytokines and Th17/Treg ratio were significantly increased in aged mice compared to young mice. The human prostate cancer cell lines (LNCaP, DU-145 and PC3) and mouse prostate cancer cell line (PTEN-CaP8) was cultured in their suitable medium as in our previous study. These cell lines were treated with the above mentioned conditioned media (Th0 and Th17) for 48 and 72 hours and harvested for subsequent experiments. When human and mouse prostate cancer cell lines were exposed to the aged Th17 conditioned media, cell proliferation, migration and invasion were significantly increased, and the pro-inflammatory NF-κB pathway in PCa cell lines was activated compared to cells exposed to young ones. In summary, these results collectively indicate that Th17 immune responses are elevated in mice in the aging process, and this age-related elevated Th17 immune responses may play an important role in prostate carcinogenesis. This work was supported by the NIH-National Institute of General Medical Sciences COBRE (2P20GM103629-06, PI: SMJ; Pilot Project PI: QZ). Citation Format: Qiuyang Zhang, Sen Liu, Zongbing You, Brian G. Rowan, S M. Jazwinski, Alun R. Wang, Leann Myers. Age-related elevated Th17 immune response contributes to prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 58.