Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR.

Androgen deprivation and immunotherapy for the treatment of prostate cancer.

Prostate cancer is the most common newly diagnosed malignancy in men, and the second most common cause of cancer-related death in the United States. The primary treatment for recurrent prostate cancer is androgen deprivation, and this therapy is typically continued lifelong for patients with metastatic prostate cancer. Androgens and androgen deprivation have profound effects on the immune system, a finding that has become more appreciated in an era where immune-based treatments for cancer are being increasingly explored. Preclinical studies suggest that androgen deprivation could potentially positively or negatively affect the use of approved immunotherapies, or those that are being developed for the treatment of prostate cancer. In this review, we provide a brief overview of the different types of androgen deprivation treatments used in the management of prostate cancer, discuss their effects on prostate tumors and the immune system and how they are being explored in combination with immunotherapy. Finally, we address some of the critical questions in the field that must be answered to identify the best approaches to combine androgen deprivation with immunotherapy for the treatment of prostate cancer.

Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate.

The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

FOXA1 and SOX9 Expression in the Developing Urogenital Sinus of the Tammar Wallaby (Macropus eugenii).

The mammalian prostate is a compact structure in humans but multi-lobed in mice. In humans and mice, FOXA1 and SOX9 play pivotal roles in prostate morphogenesis, but few other species have been examined. We examined FOXA1 and SOX9 in the marsupial tammar wallaby, Macropus eugenii, which has a segmented prostate more similar to human than to mouse. In males, prostatic budding in the urogenital epithelium (UGE) was initiated by day 24 postpartum (pp), but in the female the UGE remained smooth and had begun forming the marsupial vaginal structures. FOXA1 was upregulated in the male urogenital sinus (UGS) by day 51 pp, whilst in the female UGS FOXA1 remained basal. FOXA1 was localised in the UGE in both sexes between day 20 and 80 pp. SOX9 was upregulated in the male UGS at day 21-30 pp and remained high until day 51-60 pp. SOX9 protein was localised in the distal tips of prostatic buds which were highly proliferative. The persistent upregulation of the transcription factors SOX9 and FOXA1 after the initial peak and fall of androgen levels suggest that in the tammar, as in other mammals, these factors are required to sustain prostate differentiation, development and proliferation as androgen levels return to basal levels.