Abstract LB-322: Synergistic effects of FOXO3 and AR to increase tolerogenicity of tumor associated dendritic cells.
Authors: Thompson Matthew , Watkins Stephanie , Hurwitz Arthur A. 
Published: August 2014

The immune system has the ability to recognize and destroy cancerous cells long before they grow, multiply and form tumors. However, once tumors develop they severely suppress anti-tumor immune responses. The underlying causes of immune suppression are complex and not completely understood. Recent studies indicate that tumor-associated dendritic cells (TADC) within the tumor microenvironment (TME) are key regulators of cytotoxic T-cell (CTL)function and may serve as a critical target for immunotherapy. The TADC-T cell interaction results in T-cell tolerance that is regulated by DC expression of the transcription factor Forkhead Box O3 (FOXO3). FOXO3 is a transcriptional regulator of a variety of processes associated with cell cycle progression as well as regulation of nuclear receptors, including the androgen receptor (AR). Androgen stimulation of tumor cells has been shown to promote tumor growth and androgen deprivation therapy is the standard of care to treat aggressively growing prostate cancers. However, less is known regarding the impact of androgen signaling on immune cell function in the TME. In this study we show a potential combined effect of AR signaling and FOXO3 to promote tolerogenic functions in TADC.

Our preliminary data, using the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP), a murine model of spontaneous prostate cancer, showed that prostates in FOXO3−/− TRAMP mice grew at half the rate compared to prostate tumors of the wild type TRAMP mice, in spite of equivalent expression of SV40 TAg. Additionally, TADC that infiltrated the FOXO3−/- tumors had minimal AR expression, were capable of stimulating T cell proliferation, and most importantly, did not promote CTL tolerance. In contrast, DC purified from wild type TRAMP had increased expression of AR and FOXO3 and were highly tolerogenic. However, upon silencing FOXO3 via siRNA, tolerogenicity subsided and AR expression was down regulated. To test the effect of androgen signaling on DC function, normal prostate dendritic cells were treated with increasing doses of dihydrotestosterone (DHT). It was observed, that FOXO3 expression and tolerogenicity increased with increased concentrations of DHT and AR stimulation. Furthermore, TRAMP mice had a significant increase, over that of wild type mice, in testosterone levels in the seminal vesicle fluid (measured by ELISA) and prostate tissue (measured by RT-PCR). Surgical castration of TRAMP mice abrogated FOXO3 and AR expression and up-regulated co-stimulatory molecules and pro-inflammatory cytokines such as IL-12 in dendritic cells. These data suggest a synergistic effect between FOXO3 and AR to promote DC mediated immune suppression in the prostate TME and may be critical targets to enhance therapies in the treatment of prostate cancer.

Citation Format: Matthew Thompson, Stephanie Watkins, Arthur A. Hurwitz. Synergistic effects of FOXO3 and AR to increase tolerogenicity of tumor associated dendritic cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-322. doi:10.1158/1538-7445.AM2013-LB-322