The Journal of Clinical Investigation (May 2023)

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

  • 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

Journal volume & issue
Vol. 133, no. 9

Abstract

Read online

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.

Keywords