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.

中文翻译：

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双吲哚衍生的NR4A1拮抗剂诱导PD-L1降解并增强抗肿瘤免疫性。

PD-L1在肿瘤细胞中表达，它与PD-1的相互作用在逃避免疫监视中起着重要作用。使用PD-L1或PD-1免疫疗法抗体可以克服这一点。这项研究报告了一种针对PD-L1的新颖方法。在人乳腺癌细胞系和4T1小鼠乳腺肿瘤细胞中，PD-L1的表达受与PD-L1基因启动子近端生发中心（GC）富集区域结合的核受体NR4A1 / Sp1复合物调控。用双吲哚衍生的NR4A1拮抗剂（包括1,1-双（3'-吲哚基）-1-（3-氯-4-羟基-5-甲氧基苯基）甲烷（Cl-OCH3））处理乳腺癌细胞会降低其表达PD-L1 mRNA，启动子依赖性荧光素酶活性和蛋白质。在使用带有原位注射4T1细胞的同系小鼠模型进行的体内研究中，Cl-OCH3降低了肿瘤的生长和重量，并抑制了肺转移。Cl-OCH3还降低了CD3 + / CD4 + / CD25 + / FoxP3 +调节性T细胞的表达，并提高了Teff / Treg比率。因此，NR4A1拮抗剂的有效抗癌活性还伴随着在表达PD-L1的三阴性乳腺癌中增强的抗肿瘤免疫性，因此代表了一类模仿免疫疗法的新型药物。意义：这些发现表明，孤儿核受体NR4A1控制着PD-L1的表达并鉴定出能够破坏该调节轴的化学探针。NR4A1拮抗剂的有效抗癌活性还伴随着在表达PD-L1的三阴性乳腺癌中增强的抗肿瘤免疫力，因此代表了一类模仿免疫疗法的新型药物。意义：这些发现表明，孤儿核受体NR4A1控制着PD-L1的表达并鉴定出能够破坏该调节轴的化学探针。NR4A1拮抗剂的有效抗癌活性还伴随着在表达PD-L1的三阴性乳腺癌中增强的抗肿瘤免疫力，因此代表了一类模仿免疫疗法的新型药物。意义：这些发现表明，孤儿核受体NR4A1控制着PD-L1的表达并鉴定出能够破坏该调节轴的化学探针。