Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis

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. [Display omitted] •Human neutrophils release ELANE to selectively kill a wide range of cancer cells•ELANE’s anti-cancer function is silenced in murine neutrophils by SLPI•ELANE proteolysis liberates the CD95 death domain to selectively kill cancer cells•ELANE attenuates tumor growth and induces a CD8+ T cell-mediated abscopal effect Neutrophil-secreted elastase shows dramatic selectivity, inducing cell death in tumors and at metastatic sites in animal models while sparing proximal healthy cells.