Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Autor:	Sandoval TA; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Salvagno C; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Chae CS; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Awasthi D; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Giovanelli P; Weill Cornell Graduate School of Medical Sciences, New York, New York., Marin Falco M; Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Hwang SM; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Teran-Cabanillas E; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Suominen L; Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Yamazaki T; Department of Radiation Oncology, Weill Cornell Medicine, New York, New York., Kuo HH; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York., Moyer JE; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York., Martin ML; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York., Manohar J; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York., Kim K; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York., Sierra MA; Weill Cornell Graduate School of Medical Sciences, New York, New York., Ramos Y; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York., Tan C; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Emmanuelli A; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.; Weill Cornell Graduate School of Medical Sciences, New York, New York., Song M; Departments of Integrative Biotechnology and of Biopharmaceutical Convergence, University of Suwon, Suwon, Korea., Morales DK; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York., Zamarin D; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Frey MK; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Cantillo E; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Chapman-Davis E; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Holcomb K; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Mason CE; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York.; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, New York., Galluzzi L; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.; Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York., Ni Zhou Z; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York., Vähärautio A; Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Foundation for the Finnish Cancer Institute, Helsinki, Finland., Cloonan SM; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York.; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland., Cubillos-Ruiz JR; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.; Weill Cornell Graduate School of Medical Sciences, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Oct 04; Vol. 14 (10), pp. 1901-1921.
DOI:	10.1158/2159-8290.CD-23-1451
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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