title: Interferon gamma modulates sensitivity of CML cells to tyrosine kinase inhibitors.
abstract: Immune effector cells such as T and NK cells can efficiently eliminate tumor cells. However, when activating oncogenic signaling pathways or protective mechanisms against cell death are active, immune cells can also confer therapy resistance. Here, we analyzed the role of activated T and NK cells and released cytokines on tyrosine kinase inhibitors imatinib and nilotinib - mediated apoptosis induction and proliferation of chronic myelogenous leukemia (CML) cells. Incubation of CML cells with activated, but not with resting CD3+T cells or with activated NK cells significantly inhibited TKI-induced apoptosis induction in CML cells as quantified by nuclear fragmentation assays. Transwell experiments revealed a critical role for T or NK cell-derived cytokines for CML cell protection. Accordingly, CML cells treated with IFNγ also showed a clearly reduced sensitivity to TKI-mediated cell death induction and inhibition of proliferation. In contrast, IFNα or other pro-inflammatory mediators and cytokines, such as TNFα and GM-CSF did not impair TKI-induced apoptosis in CML cells. On a molecular level, IFNγ-exposed CML cells showed a significantly reduced caspase-3 activation and PARP-1 cleavage as well as an increased expression of anti-apoptotic molecule xIAP. Finally, IFNγ diminished TKI-induced downregulation of Jak-2 and STAT-5 phosphorylation and increased nuclear expression of RUNX-1, which may at least in part contribute to the reduced sensitivity to TKI effects. Our results demonstrate that IFNγ released by activated T or NK cells may interfere with the therapeutic effects of TKI in CML. Our findings may have important implications for the understanding of inflammation-mediated BCR-ABL independent resistance mechanisms.
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Stefanie Andrea Erika
authors.initials: SA
authors.lastname: Held
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Annkristin
authors.initials: A
authors.lastname: Heine
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Anne Ruth
authors.initials: AR
authors.lastname: Kesper
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schönberg
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Beckers
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
keywords: Chronic myelogenous leukemia; immunotherapeutic; interferon gamma; resistance; tyrosine kinase inhibitors