Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis

Cell. 2021 Jun 10;184(12):3163-3177.e21. doi: 10.1016/j.cell.2021.04.016. Epub 2021 May 7.


Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. ELANE attenuates primary tumor growth and produces a CD8+T cell-mediated abscopal effect to attack distant metastases. Porcine pancreatic elastase (ELANE homolog) resists tumor-derived protease inhibitors and exhibits markedly improved therapeutic efficacy. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy.

Keywords: CD95; cancer; histone H1; neutrophil estate; neutrophils; therapeutics; tumor immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Eosinophil Cationic Protein / metabolism
  • Histones / metabolism
  • Humans
  • Leukocyte Elastase / metabolism*
  • Mice
  • Neoplasms / enzymology*
  • Neoplasms / immunology
  • Neoplasms / pathology*
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Pancreatic Elastase / metabolism
  • Protease Inhibitors / pharmacology
  • Protein Domains
  • Protein Isoforms / metabolism
  • Proteolysis / drug effects
  • Secretory Leukocyte Peptidase Inhibitor / metabolism
  • Swine
  • fas Receptor / chemistry
  • fas Receptor / metabolism


  • Histones
  • Protease Inhibitors
  • Protein Isoforms
  • Secretory Leukocyte Peptidase Inhibitor
  • Slpi protein, mouse
  • fas Receptor
  • Eosinophil Cationic Protein
  • Pancreatic Elastase
  • ELANE protein, human
  • Elane protein, mouse
  • Leukocyte Elastase