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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #414473
Research Project: Energy Met.: Novel Approaches to Facilitating Successful Energy Regulation in Aging--Obesity & Met.: Role of Adipocyte Metabolism in the Development of Obesity and Associated Metabolic Complications

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: Ferroptosis of tumor neutrophils causes immune suppression in cancer

Author
item KIM, RINA - University Of Pennsylvania
item HASHIMOTO, AYUMI - Wistar Institute
item MARKOSYAN, NUNE - University Of Pennsylvania
item TYURIN, VLADIMIR - University Of Pittsburgh
item TYURINA, YULIA - University Of Pittsburgh
item KAR, GOZDE - Astrazeneca Pharmaceuticals
item FU, SHUYU - Wistar Institute
item SEGAL, MOHIT - Wistar Institute
item GERIQUE, LAURA GARCIA - Wistar Institute
item KOSSENKOV, ANDREW - Wistar Institute
item GEBREGZIABHER, BEREKET - University Of Pennsylvania
item TOBIAS, JOHN - University Of Pennsylvania
item HICKS, KRISTIN - Astrazeneca Pharmaceuticals
item HALPIN, REBECCA - Astrazeneca Pharmaceuticals
item CVETESIC, NEVENA - Astrazeneca Pharmaceuticals
item DENG, HUI - Wistar Institute
item DONTHIREDDY, LAXMINARASIMHA - Wistar Institute
item GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item NAM, BRIAN - Helen F Graham Cancer Center And Research Institute, Christiana Care
item VONDERHEIDE, ROBERT - University Of Pennsylvania
item NEFEDOVA, YULIZ - Wistar Institute
item KAGAN, VALERIAN - University Of Pittsburgh
item GABRILOVICH, DMITRY - Astrazeneca Pharmaceuticals

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/13/2022
Publication Date: 11/16/2022
Citation: Kim, R., Hashimoto, A., Markosyan, N., Tyurin, V.A., Tyurina, Y.Y., Kar, G., Fu, S., Segal, M., Gerique, L., Kossenkov, A., Gebregziabher, B.A., Tobias, J.W., Hicks, K., Halpin, R.A., Cvetesic, N., Deng, H., Donthireddy, L., Greenberg, A., Nam, B., Vonderheide, R.H., Nefedova, Y., Kagan, V.E., Gabrilovich, D. 2022. Ferroptosis of tumor neutrophils causes immune suppression in cancer. Nature. https://doi.org/10.1038/s41586-022-05443-0.
DOI: https://doi.org/10.1038/s41586-022-05443-0

Interpretive Summary: Cells in the body that destroy tumors in the body are called immune cells. A major problem in the development and treatment of cancers is that in the presence of cancers, immune cells die. In this manuscript we demonstrate that with cancer, immune cells undergo a specific process of death called ferroptosis. Inhibition of ferroptosis in these immune cells prevented death and were found to inhibit tumor growth. Thus, identifying nutrients that would prevent ferroptosis in immune cells could provide a novel approach to ameliorating the growth of cancers.

Technical Abstract: Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of immune responses in cancer. In this study, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC in the TME, ferroptosis markedly enhanced immunosuppression by limiting T cell activity through the release of oxygenated lipid mediators. In mice, genetic and pharmacological inhibition of ferroptosis abrogated suppressive activity of PMN-MDSC, reduced tumor progression and synergized with immune check-point blockade (ICB) to further suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promoted tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to suppress tumor progression.