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 targetingPD-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.
Original language | English (US) |
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Pages (from-to) | 1011-1023 |
Number of pages | 13 |
Journal | Cancer research |
Volume | 80 |
Issue number | 5 |
DOIs | |
State | Published - Mar 1 2020 |
Keywords
- Animals
- Antineoplastic Agents/pharmacology
- B7-H1 Antigen/immunology
- Cell Line, Tumor/transplantation
- Disease Models, Animal
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Immunotherapy/methods
- Indoles/pharmacology
- Lung Neoplasms/immunology
- Mice
- Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors
- Proteolysis/drug effects
- T-Lymphocytes, Cytotoxic/drug effects
- T-Lymphocytes, Regulatory/drug effects
- Triple Negative Breast Neoplasms/drug therapy
- Tumor Microenvironment/drug effects
ASJC Scopus subject areas
- Oncology
- Cancer Research