The Serine Protease Neutrophil Elastase Selectively Kills Tumor Cells

Optimal cancer therapies selectively kill tumor cells but spare healthy cells, making harnessing the inherent target specificity of the innate immune system an attractive strategy. Because previous research has shown that neutrophils can exhibit antitumor activity, Cui and colleagues investigated the effects of human neutrophil–conditioned medium, revealing that neutrophils secreted factors that induced apoptosis in a wide range of cancer cells. Neutrophil elastase (ELANE), a serine protease, was identified as the major secreted protein mediating cancer cell killing. Notably, this effect was specific to human neutrophils, as conditioned medium from murine neutrophils had no anticancer activity. In cancer cells, ELANE triggered a cell death program mirroring the cell death phenotype previously observed upon knockdown of FAS (encoding the Death receptor Fas, also known as CD95), suggesting that ELANE may proteolytically cleave CD95. Indeed, ELANE cleaved the C-terminal domain of CD95 and liberated the Death domain, killing cancer cells via suppression of survival pathways and induction of mitochondrial reactive oxygen species, DNA damage, and apoptosis, but remaining nontoxic to noncancer cells. DNA damage can cause apoptosis by promoting the mitochondrial translocation of histone 1 (H1), and H1 isoforms were elevated and bound to the CD95 Death domain in cancer cells, suggesting that ELANE may be selectively toxic in cancer cells due to higher H1 levels. In vivo, ELANE administration not only attenuated primary tumor growth in multiple models, but also increased cytotoxic CD8⁺ T cells and decreased tumor growth at distant metastases. Whereas in vivo efficacy of ELANE was limited by tumor-secreted protease inhibitors, porcine pancreatic elastase (PPE), an ELANE ortholog, was less susceptible to serine protease inhibition and more effective in tumor attenuation. In summary, this work suggests that further study of the ELANE–CD95–H1 axis may enable the development of novel anticancer therapies and reveals a mechanism of cancer cell–selective killing by neutrophils.

Cui C, Chakraborty K, Tang XA, Zhou G, Schoenfelt KQ, Becker KM, et al. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis. Cell 2021;184:3163–77.E21.

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