Abstract 947: Influence of abiraterone therapy on anti-tumor immunity in genetically engineered mouse prostate cancer models
Authors: Banno Eri , Velasco Marco A. De , Kura Yurie , Ando Naomi , Sato Noriko , Nozawa Masahiro , Yoshimura Kazuhiro , Sakai Kazuko , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2018

Recent evidence has suggested that androgen deprivation therapies (ADTs) can influence tumor immune responses via androgen receptor (AR) regulation. On one hand, reports have indicated that certain ADTs can compromise T cell immune responses and enhance PD-L1 immune suppression, while others indicate that ADT can enhance anti-tumor responses via modulation of the apoptotic pathway. Abiraterone is a steroidal CYP17 inhibitor approved for the treatment of late-stage metastatic castration-resistant prostate cancer. In this study we use genetically engineered mouse models of prostate cancer (GEMMs-PCa) to investigate the antitumor activity of abiraterone and its influence on tumor immunity. In a mouse Pten-deficient prostate cancer model, chronic treatment with abiraterone acetate (40 mg/kg/d, 5 days on, 2 days off) reduced prostate tumor burden by 13.1% ± 9.0 (P=0.499) after four weeks of dosing and 30.5% ± 8.1 (P=0.0275) after eight weeks. Downregulation of classical mouse Ar-responsive genes (Fkbp5, Nkx3.1, Msmb and Timp4) confirmed the inhibition AR transcriptional activity after abiraterone therapy. In a model of advanced prostate cancer, driven by the conditional inactivation of Pten and Trp53, treatment with abiraterone after surgical castration modestly improved median overall survival from 7 days to 16 days vs. castration alone (P=0.240, n=8 mice/group). qRT-PCR-based analysis of a panel of 54 immune-responsive genes, revealed distinct expression signatures in abiraterone-treated tumors compared to tumors from orchidectomized mice. Relative to orchidectomized mice, tumors from abiraterone treated mice consistently demonstrated reduced mRNA levels of the T regulatory cell gene markers Cd4, Foxp3, Cd4, Tgfb1 and Il10. Furthermore, mRNA expression levels of representative immune checkpoint genes Cd274, Pdcd1lg2, Pdcd1 and Ctla4 were also lower in abiraterone treated mice. Follow-up immunohistochemical analysis showed a 1.8-fold increase of tumor infiltrating granzyme B-positive cells in tumors of mice treated with abiraterone compared to surgical castration. Our results show that abiraterone suppressed AR transcriptional activity and reduced tumor growth and progression in GEMMs-PCa. Our data also suggests that abiraterone induces lesser immunosuppressive responses than surgical castration and supports further investigation into developing rational combinations of ADT and immunotherapy in order to enhance therapeutic responses for patients suffering with prostate cancer.

Citation Format: Eri Banno, Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sato, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuko Sakai, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Influence of abiraterone therapy on anti-tumor immunity in genetically engineered mouse prostate cancer models [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 947.