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Published on: November 16, 2016
Interferon gamma modulates sensitivity of CML cells to tyrosine kinase inhibitors
Stefanie Andrea Erika Held1, Annkristin Heine1, Anne Ruth Kesper1
1Department of Oncology, Hematology and Rheumatology, University Hospital Bonn , Bonn, Germany.
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.
Insights
Activated T and NK cells release interferon-gamma (IFNγ), which protects chronic myelogenous leukemia (CML) cells from tyrosine kinase inhibitor (TKI) therapy by reducing apoptosis and proliferation.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune effector cells, including T and NK cells, can eliminate cancer cells.
- However, immune cells can also contribute to therapy resistance by activating oncogenic signaling or cell death protective mechanisms.
- Understanding these complex interactions is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To investigate the role of activated T and NK cells and their secreted cytokines in mediating resistance to tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML).
- To elucidate the molecular mechanisms by which immune cells and cytokines influence TKI efficacy in CML.
Main Methods:
- Incubation of CML cells with activated/resting T cells and activated NK cells.
- Transwell experiments to assess the role of cell-derived cytokines.
- Nuclear fragmentation assays to quantify apoptosis.
- Analysis of caspase-3 activation, PARP-1 cleavage, xIAP expression, Jak-2/STAT-5 phosphorylation, and RUNX-1 expression.
Main Results:
- Activated T cells, but not resting T cells or activated NK cells, significantly inhibited TKI-induced apoptosis in CML cells.
- T and NK cell-derived cytokines, particularly interferon-gamma (IFNγ), were critical for CML cell protection.
- IFNγ-treated CML cells exhibited reduced sensitivity to TKIs, decreased caspase-3 activation, reduced PARP-1 cleavage, increased xIAP expression, diminished downregulation of Jak-2/STAT-5 phosphorylation, and increased RUNX-1 expression.
Conclusions:
- Interferon-gamma (IFNγ) released by activated T or NK cells can interfere with the therapeutic effects of TKIs in CML.
- IFNγ-induced molecular changes in CML cells contribute to reduced sensitivity to TKI-mediated apoptosis and proliferation inhibition.
- These findings highlight a potential inflammation-mediated, BCR-ABL independent resistance mechanism in CML, with implications for future therapeutic strategies.
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