Rina Kim

"Ferroptosis is a novel pathway for MDSC-driven immunosuppression in the TME"

Rina Kim1, Ayumi Hashimoto2, Mohit Seghal3, Yulia Tyurina4, Nune Markosyan1, John Tobias1,  Bereket Gebregziabher1, Andrew Kossenkov2, Valerian Kagan4, Yulia Nefedova2, Robert H. Vonderheide1,  Dmitry Gabrilovich5   1.Department of Medicine, Perelman School of Medicine, Center for Cellular Immunotherapies, University of  Pennsylvania Philadelphia, PA, USA; 2. The Wistar Institute, Philadelphia, PA; 3. Intas Pharmaceuticals, Ahmedabad, Gujarat, India; 4. Environmental and Occupational Health, University of Pittsburg, Pittsburg, PA; 5. AstraZeneca, Gaithersburg, MD, USA

In the tumor microenvironment (TME), myeloid-derived suppressor cells (MDSC)s function as an immunosuppressive shield that protects the tumor from the host’s immune system.  Polymorphonuclear (PMN)-MDSCs accumulate in cancer and comprise >75% of all MDSCs in the TME.  Our findings indicate that during tumor progression, tumor, but not peripheral, PMN-MDSCs spontaneously die by an iron-dependent form of non-apoptotic cell death termed ferroptosis. These ferroptotic tumor PMN-MDSCs are more immune-suppressive, partially via release of prostaglandin E2 (PGE2).  In vitro induction of tumor derived PMN-MDSC ferroptosis suppresses T cell proliferation via soluble factors. In contrast, genetic deletion of known ferroptosis inducer genes ALOX15 and ACSL4 or pharmacological inhibitor of ferroptosis (Liproxstatin-1) restore T cell proliferation rate in co-culture assays. Most importantly, Liproxstatin-1 alone suppresses implanted CT26 colon cancer growth in WT but not Rag2-/- γc-/-  hosts, and potentiates the effect of anti-PD-1 treatment. The importance of ferroptosis inhibition in tumors is further confirmed by the analysis of the human pancreatic and lung adenocarcinoma data in TCGA; in both patient datasets, ferroptosis signature correlates with PMN-MDSC markers and is associated with poor patient survival. Further investigation of the PMN-MDSC ferroptosis in cancer is expected to unravel a novel mechanism of immune suppression in the tumor TME and transform therapeutic strategies aiming to kill these cells.