Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression
Xiaobo Wang, … , Yuanyuan Zhang, Yongjun Dang
Xiaobo Wang, … , Yuanyuan Zhang, Yongjun Dang
Published March 16, 2023
Citation Information: J Clin Invest. 2023;133(9):e161929. https://doi.org/10.1172/JCI161929.
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Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression

Abstract

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.

Authors

Xiaobo Wang, Jing Huang, Fenglin Liu, Qian Yu, Ruina Wang, Jiaqi Wang, Zewen Zhu, Juan Yu, Jun Hou, Joong Sup Shim, Wei Jiang, Zengxia Li, Yuanyuan Zhang, Yongjun Dang

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Figure 5

Aurora A inhibition–induced PD-L1 expression is mediated by cGAS dephosphorylation.

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Aurora A inhibition–induced PD-L1 expression is mediated by cGAS dephosp...
(A–C) WT BxPC3 cells or CGAS–/– BxPC3 cells were treated with 1 μmol/L alisertib for 72 hours. (A) Western blot analysis of PD-L1 and cGAS protein levels. PD-L1 and cGAS were detected separately in 2 gels using the same biological samples, and GAPDH in each gel served as the loading control. qRT-PCR analysis of PDL1 (B) and IFNB (C) mRNA levels (n = 3). (D) Co-immunoprecipitation of Aurora A and cGAS. HEK293T cells were transfected with the indicated vectors encoding HA–Aurora A and Flag-cGAS. Whole-cell lysates were immunoprecipitated with anti-Flag beads, and the interactions were analyzed by Western blotting. (E) BxPC3 cells were synchronized with 10 μmol/L Ro-3306 for 16 hours and released into mitosis in the presence of alisertib at the indicated concentrations. Phosphorylation of cGAS was analyzed by Phos-tag electrophoresis. Data indicate the mean ± SD. ****P < 0.0001, by 2-way ANOVA.