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.

Isolation of polymorphonuclear neutrophils and monocytes from a single sample of human peripheral blood.

Monocytes and neutrophils are widely distributed throughout the body and play essential roles in health and disease. Here, we present a detailed protocol to isolate polymorphonuclear neutrophils and monocytes from a single sample of human peripheral blood. We have optimized several aspects of the procedure, including the density gradient, timing of each cell processing step, and the buffer/media conditions to preserve cell viability for subsequent functional assays. This protocol is reproducible and can be scaled as required for downstream applications. For complete details on the use and execution of this protocol, please refer to Cui et al. (2021).