Abstract
NK cells expressing TIM-3 show a marked increase in IFNγ production in response to acute myeloid leukemia (AML) blast cells that endogenously express Gal-9. Herein, we demonstrate that NK cell-mediated production of IFNγ, induced by TIM-3/Gal-9 interaction and released in bone marrow microenvironment, is responsible for IDO1 expression in AML blasts. IDO1-expressing AML blasts consequently down-regulate NK cell degranulation activity, by sustaining leukemia immune escape. Furthermore, the blocking of TIM-3/Gal-9 interaction strongly down-regulates IFNγ-dependent IDO1 activity. Thus, the inhibition of TIM-3/Gal-9 immune check point, which affects NK cell-dependent IFNγ production and the consequent IDO1 activation, could usefully integrate current chemotherapeutic approaches.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Blotting, Western
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Cells, Cultured
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Chromatography, High Pressure Liquid
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Enzyme-Linked Immunosorbent Assay
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Galectins / metabolism
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Hepatitis A Virus Cellular Receptor 2
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis*
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Interferon-gamma / metabolism
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / pathology
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Leukemia, Myeloid, Acute / immunology*
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Leukemia, Myeloid, Acute / metabolism
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Membrane Proteins / metabolism
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Signal Transduction / immunology*
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Tumor Escape / immunology*
Substances
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Galectins
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HAVCR2 protein, human
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Hepatitis A Virus Cellular Receptor 2
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IDO1 protein, human
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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LGALS9 protein, human
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Membrane Proteins
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Interferon-gamma