Figure S1. (a) Effect of dietary iron levels on ovarian cancer progression. Figure S2. Flow cytometry gating strategy for the analysis of peritoneal cells from mice bearing ID8Defb29/Vegfa tumors that were treated with deferiprone as single agent or in combination with cisplatin. Figure S3. (a-f) Wild-type female mice were implanted with ID8-Defb29/Vegfa tumors and treated as described in Fig 2 d. Figure S4. (a) Representative images of NKp46 staining on the entire omentum. Figure S5. (a) MTT assays for ID8-Defb29/Vegfa, PPNM, and MP cells treated with different concentrations of deferiprone for 12, 24, and 48 hours. Figure S6. (a) Human ovarian cancer cell lines were treated with deferiprone for 48 hours and expression of the indicated genes was analyzed by qRT-PCR. Colors indicate fold change (FC) upon deferiprone treatment compared with vehicle control. Figure S7. (a-b) Mitochondrial iron was traced using mito-ferrogreen in iron-overloaded ID8-Defb29/Vegfa cells that were exposed to deferiprone (100 µM) or vehicle control. Figure S8. (a) Schematic representation of treatment regimens under IFNAR1 blockade related to Fig. 6 a-c.
Funding
The Sigrid Jusélius Foundation
The Cancer Foundation Finland
PerMed JTC2020 PARIS/Academy of Finland
Foundation for the Finnish Cancer Institute
Marie Skłodowska-Curie grant
The Ovarian Cancer Research Alliance
National Cancer Center, Korea
American Association for Cancer Research (AACR)
Cancer Research Institute (CRI)
Stand Up To Cancer (SU2C)
National Institutes of Health (NIH)
National Research Foundation of Korea (NRF)
U.S. Department of Defense (DOD)
ARTICLE ABSTRACT
Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell–centric modalities.Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy.See related commentary by Bell and Zou, p. 1771
