Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.
Tito A SandovalCamilla SalvagnoChang-Suk ChaeDeepika AwasthiPaolo GiovanelliMatias M FalcoSung-Min HwangElí Terán-CabanillasLasse SuominenTakahiro YamazakiHui-Hsuan KuoJenna E MoyerMaria Laura MartinJyothi ManoharKihwan KimMaria A SierraYusibeska RamosChen TanAlexander EmmanuelliMinkyung SongDiana K MoralesDmitriy ZamarinMelissa K FreyEvelyn CantilloEloise Chapman-DavisKevin HolcombChristopher E MasonLorenzo GalluzziZhen Ni ZhouAnna VaharautioSuzanne M CloonanJuan R Cubillos-RuizPublished in: Cancer discovery (2024)
Iron accumulation in tumors contributes to disease progression and chemoresistance. While 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 towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (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.
Keyphrases
- immune response
- nk cells
- mitochondrial dna
- iron deficiency
- dna damage
- dendritic cells
- small cell lung cancer
- squamous cell carcinoma
- oxidative stress
- copy number
- toll like receptor
- radiation therapy
- young adults
- gene expression
- dna repair
- transcription factor
- rectal cancer
- genome wide
- free survival
- squamous cell
- smoking cessation
- childhood cancer