Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells.

Fatehchand K, McMichael EL, Reader BF, Fang H, Santhanam R, Gautam S, Elavazhagan S, Mehta P, Buteyn NJ, Merchand-Reyes G, Vasu S, Mo X, Benson DM Jr, Blachly JS, Carson WE 3rd, Byrd JC, Butchar JP, Tridandapani S
J Biol Chem 291 25656-25666 12/02/2016

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 by

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