4.8 Article

Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 133, 期 9, 页码 -

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI161929

关键词

-

向作者/读者索取更多资源

Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. However, this study found that the Aurora A inhibitor alisertib upregulated PD-L1 expression, reducing antitumor immunity and paradoxically inhibiting the antitumor effects of alisertib.
Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-KB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据