Rina Kim (Mentor: Robert Vonderheide MD, DPhil)

“Ferroptotic death of tumor associated neutrophils is immunosuppressive and promotes tumor growth”

Rina Kim, Ayumi Hashimoto, Nune Markosyan, Mohit Sehgal, Vladimir A. Tyurin, Yulia Y. Tyurina, Andrew Kossenkov, Bereket A. Gebregziabher,  John W Tobias, Laura Garcia Gerique, Shuyu Fu, Robert H. Vonderheide, Yulia Nefedova, Valerian E. Kagan and Dmitry Gabrilovich

Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of the immune response in cancer.  In this study, we found that PMN-MDSC in the tumor microenvironment (TME) spontaneously die by a novel type of cell death called ferroptosis.  While decreasing  the presence of PMN-MDSC in the TME, ferroptosis significantly enhanced immune-suppressive, T cell limiting activity of these cells due to release of oxygenated lipid mediators.  Inhibition of ferroptosis 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 immune-suppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to suppress the  tumor progression.