Abstract F2-2: Neutrophil elastase and anti-tumor effects

Abstract

Abstract 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. On a molecular level, ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. In pre-clinical models, ELANE attenuates primary tumor growth and produces a CD8+ T cell-mediated abscopal effect to attack distant metastases, therapeutic effects that are improved on by porcine pancreatic elastase, an ELANE homolog that better resists protease inhibitors in the tumor microenvironment. 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. Citation Format: Lev Becker. Neutrophil elastase and anti-tumor effects [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F2-2.