Abstract
In this study, we describe a novel kinase inhibitor AX-0085 which can suppress the induction of PD-L1 expression by Interferon-γ (IFN-γ) in lung adenocarcinoma (LUAD) cells. AX-0085 effectively blocks JAK2/STAT1 signaling initiated by IFN-γ treatment and prevents nuclear localization of STAT1. Importantly, we demonstrate that AX-0085 reverses the IFN-γ-mediated repression of T cell activation in vitro and enhances the anti-tumor activity of anti-PD-1 antibody in vivo when used in combination. Finally, transcriptomic analyses indicated that AX-0085 is highly specific in targeting the IFN-γ-pathway, thereby raising the possibility of applying this reagent in combination therapy with checkpoint inhibitor antibodies. It may be particularly relevant in cases in which PD-L1-mediated T cell exhaustion leads to immunoevasive phenotypes.
Keywords:
AX-0085; PD-L1; cancer immunotherapy; immune checkpoint; lung adenocarcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma of Lung / genetics
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Adenocarcinoma of Lung / immunology*
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Adenocarcinoma of Lung / pathology
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Animals
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B7-H1 Antigen / immunology
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B7-H1 Antigen / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Interferon-gamma / pharmacology*
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Janus Kinase 2 / metabolism
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology*
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Lung Neoplasms / pathology
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred C57BL
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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STAT1 Transcription Factor / metabolism
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Signal Transduction / drug effects
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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Treatment Outcome
Substances
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B7-H1 Antigen
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Protein Kinase Inhibitors
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STAT1 Transcription Factor
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STAT1 protein, human
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Interferon-gamma
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JAK2 protein, human
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Janus Kinase 2