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

• DOI: 10.1038/s41467-021-24769-3
• Publication Date: 2021-07-27T10:03:36Z
• Authors: 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; Tingbo Liang
• Keywords: Immune checkpoint; Cancer Immunotherapy

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