A bis-indole-derived NR4A1 antagonist induces PD-L1 degradation and enhances antitumor immunity

Keshav Karki, Gus A. Wright, Kumaravel Mohankumar, Un Ho Jin, Xing Han Zhang, Stephen Safe

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 languageEnglish (US)
Pages (from-to)1011-1023
Number of pages13
JournalCancer research
Issue number5
StatePublished - Mar 1 2020


  • 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


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