Abstract 1438: Acute immune responses to apalutamide in mouse <i>Pten</i>-deficient prostate cancer
Authors: Marco A. De Velasco, Yurie Kura, Naomi Ando, Kazuko Sakai, Nobutaka Shimizu, Eri Banno, Masahiro Nozawa, Kazuhiro Fujita, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2021)

Abstract The androgen receptor (AR) is a major therapeutic target for human prostate cancer and therapies targeting the AR pathway also impact local and systemic immunity. However, the influences over host immune function vary depending on the type of AR treatment. Androgen deprivation (AD) can improve immune cell infiltration by enhancing T cell trafficking, but it also attracts immunosuppressive myeloid cells and regulatory T cells. We previously showed that chronic dosing of apalutamide, an oral nonsteroidal AR antagonist, was effective in suppressing tumor growth in a preclinical mouse models of Pten-deficient prostate cancer and also changed the composition of the tumor immune microenvironment improving cytotoxic T cell activity. Moreover, we also showed that using AD as neoadjuvant therapy improved the antitumor activity and immune responses of combined JAK/PD-L1 blockade, whereas administered as concurrent or adjuvant therapy was ineffective. Our aim in this study is to determine the potential of using apalutamide in as combination therapy with immunotherapy and immune modulating agents. For this we have characterized the acute immune modulatory activity of apalutamide on mouse Pten-deficient and compared its activity against that of AD. Conditional prostate specific Pten/Trp53 double knockout mice were orchidectomized or treated with apalutamide (30 mg/kg/D) for five days. Tumor samples and lymphoid organs were collected and processed for immune profiling using a qRT-PCR focused panel, flow cytometry and/or immunohistochemistry. Prostates from orchidectomized mice tended to be smaller however there was no decrease in size for apalutamide treated mice. Notably, thymuses were significantly enlarged in both orchidectomized and apalutamide treated mice compared to control. Genes related to antigen presenting/dendritic cell (APC/DC) and activated DC were greater in apalutamide treated mice compared to vehicle treated or surgically castrated mice. This finding was consistent with an increased abundance of MHC-IIhi/CD80+ migratory DCs (CD11c+/XCR1+) in tumors of apalutamide treated mice. Tumor associated macrophage infiltration was also greater in apalutamide treated mice. Granulocyte infiltration was significantly greater after both castration and apalutamide therapy however the proportion of mature granulocytes was higher in castrated mice. T cell infiltration was comparable between orchidectomized and apalutamide treated mice, and regulatory T cell activity was increased in both groups compared to controls, but to a higher degree in orchidectomized mice. In summary, this provides critical data that will be essential when developing rational combinations with additional immunotherapies and immunomodulatory agents. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Kazuko Sakai, Nobutaka Shimizu, Eri Banno, Masahiro Nozawa, Kazuhiro Fujita, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Acute immune responses to apalutamide in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1438.