FOXP3型
癌症研究
白细胞介素2受体
免疫疗法
PD-L1
化学
癌症免疫疗法
荧光素酶
转移
细胞凋亡
免疫系统
细胞毒性T细胞
癌症
医学
癌细胞
体内
细胞生物学
生物
T细胞
免疫学
转染
内科学
生物化学
基因
作者
Keshav Karki,Gus A. Wright,Kumaravel Mohankumar,Un Ho Jin,Xing Han Zhang,Stephen Safe
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2020-03-01
卷期号:80 (5): 1011-1023
被引量:14
标识
DOI:10.1158/0008-5472.can-19-2314
摘要
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.
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