ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors

Cancer Res. 2015 Mar 1;75(5):824-34. doi: 10.1158/0008-5472.CAN-14-1643. Epub 2015 Jan 15.


The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by MHC class I (MHC-I) molecules. Herein, we demonstrate that genetic or pharmacological inhibition of ERAP1 on human tumor cell lines perturbs their ability to engage several classes of inhibitory receptors by their specific ligands, including killer cell Ig-like receptors (KIR) by classical MHC-I-peptide (pMHC-I) complexes and the lectin-like receptor CD94-NKG2A by nonclassical pMHC-I complexes, in each case leading to natural killer (NK) cell killing. The protective effect of pMHC-I complexes could be restored in ERAP1-deficient settings by the addition of known high-affinity peptides, suggesting that ERAP1 was needed to positively modify the affinity of natural ligands. Notably, ERAP1 inhibition enhanced the ability of NK cells to kill freshly established human lymphoblastoid cell lines from autologous or allogeneic sources, thereby promoting NK cytotoxic activity against target cells that would not be expected because of KIR-KIR ligand matching. Overall, our results identify ERAP1 as a modifier to leverage immune functions that may improve the efficacy of NK cell-based approaches for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / genetics
  • Aminopeptidases / immunology*
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Killer Cells, Natural / immunology*
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Medulloblastoma / immunology
  • Minor Histocompatibility Antigens
  • NK Cell Lectin-Like Receptor Subfamily C / immunology
  • NK Cell Lectin-Like Receptor Subfamily D / immunology
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Receptors, KIR2DL1 / immunology
  • Receptors, KIR2DL3 / immunology
  • Receptors, KIR3DL1 / immunology
  • Receptors, Natural Killer Cell / immunology*
  • Sulfhydryl Compounds / pharmacology


  • Enzyme Inhibitors
  • KIR2DL1 protein, human
  • KIR2DL3 protein, human
  • KIR3DL1 protein, human
  • Minor Histocompatibility Antigens
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • RNA, Small Interfering
  • Receptors, KIR2DL1
  • Receptors, KIR2DL3
  • Receptors, KIR3DL1
  • Receptors, Natural Killer Cell
  • Sulfhydryl Compounds
  • leucinethiol
  • Aminopeptidases
  • ERAP1 protein, human
  • Leucine