Ferroptosis of tumour neutrophils causes immune suppression in cancer

Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Gozde Kar, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Andrew Kossenkov, Bereket A. Gebregziabher, John W. Tobias, Kristin Hicks, Rebecca A. Halpin, Nevena Cvetesic, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Robert H. Vonderheide, Yulia Nefedova, Valerian E. Kagan and Dmitry I. Gabrilovich ()
Additional contact information
Rina Kim: University of Pennsylvania
Ayumi Hashimoto: AstraZeneca
Nune Markosyan: University of Pennsylvania
Vladimir A. Tyurin: University of Pittsburgh
Yulia Y. Tyurina: University of Pittsburgh
Gozde Kar: AstraZeneca
Shuyu Fu: Wistar Institute
Mohit Sehgal: Wistar Institute
Laura Garcia-Gerique: Wistar Institute
Andrew Kossenkov: Wistar Institute
Bereket A. Gebregziabher: University of Pennsylvania
John W. Tobias: University of Pennsylvania
Kristin Hicks: AstraZeneca
Rebecca A. Halpin: AstraZeneca
Nevena Cvetesic: AstraZeneca
Hui Deng: Wistar Institute
Laxminarasimha Donthireddy: Wistar Institute
Andrew Greenberg: Tufts University
Brian Nam: Christiana Care
Robert H. Vonderheide: University of Pennsylvania
Yulia Nefedova: Wistar Institute
Valerian E. Kagan: University of Pittsburgh
Dmitry I. Gabrilovich: AstraZeneca

Nature, 2022, vol. 612, issue 7939, 338-346

Abstract: Abstract 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 mice1,2. 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 immunity3–5. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05443-0

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