Title: A Bis-Indole-Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Antitumor Immunity.

Authors: Karki, Keshav; Wright, Gus A; Mohankumar, Kumaravel; Jin, Un-Ho; Zhang, Xing-Han; Safe, Stephen

Published In Cancer Res, (2020 03 01)

Abstract: PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells, PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal germinal center (GC)-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole-derived NR4A1 antagonists including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoter-dependent luciferase activity, and protein. In in vivo studies using a syngeneic mouse model bearing orthotopically injected 4T1 cells, Cl-OCH3 decreased tumor growth and weight and inhibited lung metastasis. Cl-OCH3 also decreased expression of CD3+/CD4+/CD25+/FoxP3+ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anticancer activities of NR4A1 antagonists are also accompanied by enhanced antitumor immunity in PD-L1-expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy. SIGNIFICANCE: These findings show that the orphan nuclear receptor NR4A1 controls PD-L1 expression and identify a chemical probe capable of disrupting this regulatory axis.

PubMed ID: 31911554

MeSH Terms: Animals; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/therapeutic use; B7-H1 Antigen/immunology; B7-H1 Antigen/metabolism*; Cell Line, Tumor/transplantation; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic/drug effects; Gene Expression Regulation, Neoplastic/immunology; Humans; Immunotherapy/methods; Indoles/pharmacology; Indoles/therapeutic use; Lung Neoplasms/immunology; Lung Neoplasms/prevention & control*; Lung Neoplasms/secondary; Mice; Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors*; Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism; Proteolysis/drug effects; T-Lymphocytes, Cytotoxic/drug effects; T-Lymphocytes, Cytotoxic/immunology; T-Lymphocytes, Regulatory/drug effects; T-Lymphocytes, Regulatory/immunology; Triple Negative Breast Neoplasms/drug therapy*; Triple Negative Breast Neoplasms/immunology; Triple Negative Breast Neoplasms/pathology; Tumor Microenvironment/drug effects; Tumor Microenvironment/immunology