Androgen-deprivation therapy (ADT) is the mainstay treatment for advanced metastatic prostate cancer. Treatments targeting androgen receptor (AR) signaling by androgen withdrawal or AR antagonists have been implemented in clinical practice, and clinical trials evaluating treatment combinations with immunotherapy are ongoing. However, AR expression is not limited to prostate epithelial cells and is expressed in several cell types including stromal and immune cells. Preclinical studies have shown that ADT can positively or negatively influence antitumor immunity depending on the treatment approach. To gain insights into the influence of ADT on tumor immunity, we compared surgical castration (Cast), AR-antisense oligonucleotide (ISIS581088, ISI), nonsteroidal antiandrogen (apalutamide, Apa) and hormonal antiandrogen (chlormadinone acetate, CMA) treatments in a mouse model of Pten-deficient prostate cancer. Conditional PSACre/Ptenf/f mice were treated for eight weeks and the antitumor activity and effects on immune organs were assessed. Compared to control mice, treatments with Cast, ISI, Apa and CMA significantly reduced tumor growth by 69.8%, 65.0%, 37.8%, and 40.8%, respectively, P<0.001. A significant enlargement of the thymus was seen in Cast (125 %) and Apa (45.8%)-treated mice whereas significant involution occurred after ISI (-73.3%) and CMA (-60.0%) treatments. Enlargement of spleen was noted in Cast (201.2%, P=0.009) ISI (96.3%, P=0.004) and Apa (55%, P=0.256)-treated mice. Draining lymph nodes were significantly larger in mice treated with ISI (48%, P=0.027), whereas their size decreased after treatment with Apa (-31.6%) and CMA (-15.4%). Focused gene expression profiling of immune and AR responsive genes by qRT-PCR array was performed on prostate tumor samples. Functional enrichment analysis of differentially expressed genes indicated distinct patterns of expression between treatments. Overall, the expression signatures of Cast and ISI were more closely concordant than those of Apa and CMA. Notably, genes associated with abnormal immune tolerance were enriched in Cast, Apa and CMA treatment groups. Genes associated with abnormal T-cell proliferation and PD-1 signaling were enriched in castrated mice. Our study shows that the AR signaling axis influences immune modulation and its effects on tumor immunity vary greatly depending on the pharmacologic approach for AR signaling inhibition. Rational combinations of ADT and immunotherapy will have to be carefully characterized and optimized in order to achieve their full therapeutic potential.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Kazuko Sakai, Barry R. Davies, Youngsoo Kim, A. Robert MacLeod, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Treatment-dependent effects of androgen receptor signaling suppression on immune modulation in mouse Pten-deficient prostate cancer [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 1715.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.