Ferroptosis of tumour neutrophils causes immune suppression in cancer

• Published in: Nature (London) Vol. 612; no. 7939; pp. 338 - 346
• Main Authors: Kim, Rina, Hashimoto, Ayumi, Markosyan, Nune, Tyurin, Vladimir A., Tyurina, Yulia Y., Kar, Gozde, Fu, Shuyu, Sehgal, Mohit, Garcia-Gerique, Laura, Kossenkov, Andrew, Gebregziabher, Bereket A., Tobias, John W., Hicks, Kristin, Halpin, Rebecca A., Cvetesic, Nevena, Deng, Hui, Donthireddy, Laxminarasimha, Greenberg, Andrew, Nam, Brian, Vonderheide, Robert H., Nefedova, Yulia, Kagan, Valerian E., Gabrilovich, Dmitry I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.12.2022; Nature Publishing Group
• Subjects: 13/106; 13/2; 13/21; 13/31; 13/51; 45/77; 45/90; 45/91; 631/250/580; 631/67/580/1884; Animal models; Animals; Apoptosis; Cancer; Cell death; Ferroptosis; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune system; Immunocompetence; Immunodeficiency; Leukocytes (neutrophilic); Lipids; Lymphocytes; Lymphocytes T; Mice; Microenvironments; multidisciplinary; Neoplasms; Neutrophils; Peptides; Peroxidation; Pharmacology; Phospholipids; Science; Science (multidisciplinary); Spleen; Suppressor cells; T cell receptors; Tumor Microenvironment; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05443-0

Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice 1 , 2 . This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity 3 – 5 . Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression. Pathologically activated neutrophils, termed myeloid-derived suppressor cells, in the tumour microenvironment spontaneously undergo ferroptosis, which negatively regulates anti-tumour immunity through the release of oxygenated lipids, therefore limiting the activity of human and mouse T cells.