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

Nat Commun. 2021 Jul 27;12(1):4536. doi: 10.1038/s41467-021-24769-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • B7-H1 Antigen / metabolism*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunity*
  • Male
  • Mice, Nude
  • Middle Aged
  • Models, Biological
  • NIMA-Related Kinases / antagonists & inhibitors*
  • NIMA-Related Kinases / deficiency
  • NIMA-Related Kinases / genetics
  • NIMA-Related Kinases / metabolism
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • Phosphoserine / metabolism
  • Prognosis
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Stability
  • Proteolysis
  • Ubiquitination

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Phosphoserine
  • NEK2 protein, human
  • NIMA-Related Kinases
  • Proteasome Endopeptidase Complex