Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis.

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Cancer's genetic diversity and host cell similarity challenge broad therapeutic development.
• The innate immune system's capacity to target cancer cells selectively remains largely unexplored.

Purpose of the Study:

• To investigate the potential of innate immunity, specifically neutrophil elastase (ELANE), as a broad anti-cancer therapeutic.
• To elucidate the mechanism by which ELANE selectively eliminates cancer cells.

Main Methods:

• Analysis of human and murine neutrophil function.
• Investigation of neutrophil elastase (ELANE) activity against various cancer cell types.
• ELANE's mechanism of action involving CD95 death domain and histone H1 isoforms.
• Assessment of ELANE's therapeutic efficacy in primary tumor growth and abscopal effects.
• Evaluation of porcine pancreatic elastase as a therapeutic alternative.

Main Results:

• Human neutrophils release active ELANE, selectively killing diverse cancer cells while sparing non-cancer cells.
• ELANE liberates the CD95 death domain, interacting with histone H1 isoforms for cancer cell eradication.
• ELANE treatment reduced primary tumor growth and induced a CD8+ T cell-mediated abscopal effect against distant metastases.
• Porcine pancreatic elastase demonstrated enhanced therapeutic efficacy and resistance to tumor-derived protease inhibitors.

Conclusions:

• ELANE exhibits selective cytotoxicity against genetically diverse cancer cells with minimal host toxicity.
• ELANE's mechanism offers a novel therapeutic strategy for broad-spectrum cancer treatment.
• ELANE and its analogs represent promising candidates for developing novel anti-cancer therapies.