Abstract 1838: Immunomodulatory effects of curcumin monoglucuronide on PD1 immune checkpoint blockade in mouse Pten-null prostate cancer
Authors: Kura Yurie , De Velasco Marco A. , Sakai Kazuko , Ando Naomi , Sako Noriko , Fujita Kazutoshi , Banno Eri , Mori Yasunori , Hashimoto Mamoru , Nozawa Masahiro , Yoshimura Kazuhiro , Kakeya Hideaki , Nishio Kazuto , Uemura Hirotsugu 
Published: June 2023

Abstract
Prostate cancer is notoriously resistant to immune checkpoint blockade (ICB) immunotherapy due to its immunosuppressive tumor microenvironment (TME). Thus, reprograming the TME could improve antitumor immune responses to ICB. Curcumin is a naturally derived compound with chemopreventive and immunomodulatory properties, however, its potential is limited due to its poor bioavailability. Curcumin monoglucuronide (CMG) is a water-soluble prodrug with improved bioavailability over free-form of curcumin. We previously demonstrated the immunomodulatory potential of CMG in a transgenic mouse model of Pten-null prostate cancer, here we examine its ability to improve the antitumor immune response to ICB of the programmed death cell protein 1 (PD1). Thirty-two-week-old PSA-Cre/Ptenf/f knockout (KO) mice were treated with anti-PD1 (aPD1) blocking antibody, CMG alone and in combination for 17 days weeks. Antitumor responses were determined by prostate weight, histology, and cancer proliferation and apoptosis by quantitative immunohistochemistry (qIHC). Immune responses were assessed by focused panel qRT-PCR, qIHC, and flow cytometric (FC) analysis. Systemic immune responses were assessed by FC analysis if peripheral blood and secondary lymphoid organs. Short-term dosing of aPD1 alone or in combination did not affect tumor burden as assessed by a reduction of prostate weight, however, histological analysis revealed that mice treated with CMG/aPD1 exhibited an increase in the proportion of edematous dilated glands and a non-significant reduction of solid tumor. Mice treated with CMG/aPD1 showed a significant reduction of s cancer cell proliferation (Ki67) and mice treated with CMG/aPD1 showed a 1.5-fold increase in cancer cell apoptosis. Gene expression analysis indicated upregulation of genes associated with NKT, NK and dendritic cells with combination therapy. FC and qIHC analysis indicated that T cell activation and T cell cytotoxicity was improved when CMG was administered together with aPD-1. Systemically, treatments with PD-L1 alone or in combination with CMG were associated with increased circulating myeloid-derived suppressor cells (MDSCs). Our findings provide preclinical evidence for the antitumor and immune modulatory activity of CMG in mouse Pten-deficient prostate cancer and supports further study to evaluate long-term therapy and explore additional treatment combinations.
Citation Format: Yurie Kura, Marco A. De Velasco, Kazuko Sakai, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Eri Banno, Yasunori Mori, Mamoru Hashimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Hideaki Kakeya, Kazuto Nishio, Hirotsugu Uemura. Immunomodulatory effects of curcumin monoglucuronide on PD1 immune checkpoint blockade in mouse Pten-null prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1838.