Abstract B41: Bis-indole derived NR4A1 antagonist induces PD-L1 degradation and enhances antitumor immunity

Abstract

Abstract PD-L1 is expressed in tumor cells and interaction with PD-1 in immune cells plays an important role in evading immune surveillance, and this can be overcome by immunotherapy using antibodies against PD-L1 or PD-1. This study reports a novel approach for targeting PD-L1. Results of RNA interference, chromatin immunoprecipitation, and mutational analysis show that in MDA-MB-231 and other human breast cancer cells and 4T1 mouse mammary tumor cells the PD-L1 expression is regulated by the nuclear receptor 4A1/NR4A1/Sp1 complex bound to the proximal GC-rich region of the PD-L1 gene promoter. Treatment breast cancer cells with bis-indole derived NR4A1 antagonists including 1,1-bis(3´-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (ClOCH3) decreased expression of PD-L1 mRNA promoter-dependent luciferase activity and protein. In vivo studies using a syngeneic mouse model with Balb/c mice bearing orthotopically injected 4T1 cells showed that 2.5, 7.5, and 12.5 mg/kg/d of ClOCH3 decreased tumor growth and weight and inhibited lung metastasis. The NR4A1 antagonist ClOCH3 also decreased expression of CD+/CD4+/CD25+/FoxP3 regulatory T cells in tumor-infiltrating lymphocytes and increased Teff/Treg ratios. Thus, the potent anticancer activities of NR4A1 antagonists are also accompanied by enhanced antitumor immunity in breast cancer and represent a novel class of drugs that are immunotherapy mimics. Note:This abstract was not presented at the conference. Citation Format: Keshav Karki, Gus Wright, Jin Un-Ho, Kumaravel Mohankumar, Xing Zhang, Stephen Safe. Bis-indole derived NR4A1 antagonist induces PD-L1 degradation and enhances antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B41.