Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.
Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.
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DOI：
10.1172/jci161929
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发表时间：
2023-05-01
期刊：
影响因子：
--
通讯作者：
Dang Y
中科院分区：
文献类型：
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作者：
Wang X;Huang J;Liu F;Yu Q;Wang R;Wang J;Zhu Z;Yu J;Hou J;Shim JS;Jiang W;Li Z;Zhang Y;Dang Y
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-κB 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.
