NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1

Xiaozhen Zhang, Xing Huang (), Jian Xu, Enliang Li, Mengyi Lao, Tianyu Tang, Gang Zhang, Chengxiang Guo, Xiaoyu Zhang, Wen Chen, Dipesh Kumar Yadav, Xueli Bai () and Tingbo Liang ()
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Xiaozhen Zhang: Zhejiang University
Xing Huang: Zhejiang University
Jian Xu: Zhejiang University
Enliang Li: Zhejiang University
Mengyi Lao: Zhejiang University
Tianyu Tang: Zhejiang University
Gang Zhang: Zhejiang University
Chengxiang Guo: Zhejiang University
Xiaoyu Zhang: Zhejiang University
Wen Chen: Zhejiang University
Dipesh Kumar Yadav: Zhejiang University
Xueli Bai: Zhejiang University
Tingbo Liang: Zhejiang University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically “hot” pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.

Date: 2021
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DOI: 10.1038/s41467-021-24769-3

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