title: Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells.
abstract: Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFNγ promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFNγ drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1-related markers HLA-DR and CD86, as well as of FcγRI, which mediates effector responses to therapeutic antibodies. Importantly, IFNγ was able to up-regulate CD38, the target of the therapeutic antibody daratumumab. Because the antigen (CD38) and effector receptor (FcγRI) were both simultaneously up-regulated on the AML blasts, we tested whether IFNγ treatment of the AML cell lines THP-1 and MV4-11 could stimulate them to target one another after the addition of daratumumab. Results showed that IFNγ significantly increased daratumumab-mediated cytotoxicity, as measured both by51Cr release and lactate dehydrogenase release assays. We also found that the combination of IFNγ and activation of FcγR led to the release of granzyme B by AML cells. Finally, using a murine NSG model of subcutaneous AML, we found that treatment with IFNγ plus daratumumab significantly attenuated tumor growth. Taken together, these studies show a novel mechanism of daratumumab-mediated killing and a possible new therapeutic strategy for AML.
authors: From the Medical Scientist Training Program.|Biomedical Sciences Graduate Program.|Department of Internal Medicine.
authors: Kavin
authors: K
authors: Fatehchand
authors: Biomedical Sciences Graduate Program.|Department of Internal Medicine.
authors: Elizabeth L
authors: EL
authors: McMichael
authors: Department of Internal Medicine.
authors: Brenda F
authors: BF
authors: Reader
authors: Department of Internal Medicine.
authors: Huiqing
authors: H
authors: Fang
authors: Department of Internal Medicine.
authors: Ramasamy
authors: R
authors: Santhanam
authors: Department of Internal Medicine.
authors: Shalini
authors: S
authors: Gautam
authors: Department of Internal Medicine.
authors: Saranya
authors: S
authors: Elavazhagan
authors: Department of Internal Medicine.
authors: Payal
authors: P
authors: Mehta
authors: Molecular, Cellular, and Developmental Biology Program, and.
authors: Nathaniel J
authors: NJ
authors: Buteyn
authors: Molecular, Cellular, and Developmental Biology Program, and.
authors: Giovanna
authors: G
authors: Merchand-Reyes
authors: Department of Internal Medicine.
authors: Sumithira
authors: S
authors: Vasu
authors: Center for Biostatistics, Ohio State University, Columbus, Ohio 43210.
authors: Xiaokui
authors: X
authors: Mo
authors: Department of Internal Medicine.
authors: Don M
authors: DM
authors: Benson
authors: Department of Internal Medicine.
authors: James S
authors: JS
authors: Blachly
authors: From the Medical Scientist Training Program.|Biomedical Sciences Graduate Program.|Department of Internal Medicine.
authors: William E
authors: WE
authors: Carson
authors: From the Medical Scientist Training Program.|Biomedical Sciences Graduate Program.|Department of Internal Medicine.
authors: John C
authors: JC
authors: Byrd
authors: Department of Internal Medicine, butchar.2@osu.edu.
authors: Jonathan P
authors: JP
authors: Butchar
authors: From the Medical Scientist Training Program, tridandapani.2@osu.edu.|Biomedical Sciences Graduate Program.|Department of Internal Medicine.|Molecular, Cellular, and Developmental Biology Program, and.
authors: Susheela
authors: S
authors: Tridandapani
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D003603:Cytotoxins; C573415:IFNG protein, human; D009363:Neoplasm Proteins; D017452:Receptors, IgG; C556306:daratumumab; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes
keywords: Fc receptor; antibody; interferon; signal transduction; tumor immunology