Immune checkpoint blockade with antibodies aimed at enhancing antitumor immunity have become an attractive therapeutic option. Establishing immunocompetent and clinically relevant models that predict treatment response is essential for the development of novel immunotherapies. To gain better insights into the preclinical evaluation of novel immunotherapeutic strategies, we used genetically engineered mouse models of PTEN-deficient prostate cancer. We first analyzed the transcriptome in castration-naïve prostate tumors and the progression to castration-resistant disease. Comparative analyses were performed between age-matched normal prostate and PTEN-/- prostate tumor samples from castration-naïve mice and, at 4 weeks (castration-sensitive) and 10 weeks (castration-resistant) post-surgical castration. Pathway and gene-set enrichment analysis indicated that abnormal tumor immunity was strongly associated with the progression to castration resistance. Chemokine signaling, B cell receptor and T cell receptor signaling pathways were among the top dysregulated pathways, and gene signatures of suppressed tumor immunity were enriched in castration-resistant tumors. Higher expression patterns of the programmed cell death protein 1(PD-1) and its ligand (PD-L1) were observed in castration-resistant tumors compared to castration-naïve tumors. We also characterized immune expression profiles in more aggressive tumors from PTEN/P53 double knockout (DKO) mice. PD-L1 was strongly expressed cancer cells, but a higher presence of PD-1+, CD45+ and F4/80+ stromal infiltrating immune cells in was observed in castration-resistant tumors. PD-1/PD-L1 blockade with antibodies against mouse PD-L1 increased CD45+ tumor infiltrating lymphocytes (TILs) in an early model of PTEN/P53-deficient castration-resistant prostate cancer. PTEN/P53-DKO mice with advanced castration-naïve prostate cancer tended to experienced longer overall survival after treatment with PD-1/PD-L1 blockade compared to vehicle and isotype controls, median survival 23, 14 and 11 days, respectively, P=0.458. A higher number of CD45+ TILs was observed in tumors of mice receiving the anti-PD-L1 treatment. Interim analysis of PD-1/PD-L1 blockade on a model of advanced PTEN/P53-deficient castration resistant prostate cancer (CRPC) has thus far shown that mice receiving treatment experience significantly longer survival (P=0.017, median survival not yet reached). Our findings show that castration-resistance promotes tumor immune suppression in mouse PTEN-deficient prostate cancer and suggest that this phenomenon can be reversed pharmacologically with anti-PD-L1 blockade. Thus, we provide preclinical evidence for immune checkpoint blockade as a potentially promising prostate cancer therapy.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sato, Kazuko Sakai , Barry R. Davies, Koichi Sugimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio , Hirotsugu Uemura. PD-L1 blockade in preclinical models of PTEN-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4702. doi:10.1158/1538-7445.AM2017-4702

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.