Abstract
The farnesoid X receptor (FXR) regulates inflammation and immune responses in a subset of immune-mediated diseases. We previously reported that FXR expression promotes tumor cell proliferation in non-small cell lung cancer (NSCLC). Here we study the relevance of FXR to the immune microenvironment of NSCLC. We found an inverse correlation between FXR and PD-L1 expression in a cohort of 408 NSCLC specimens; from this, we identified a subgroup of FXRhighPD-L1low patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXRhighPD-L1low NSCLC cell lines, effector function and proliferation of CD8+ T cell in vitro are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXRhighPD-L1low subtype in which FXR suppresses tumor-infiltrating immune cells. Anti-PD-1 therapy was effective against FXRhighPD-L1low mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXRhighPD-L1low NSCLC subtype and provide translational insights into therapeutic response in PD-L1low NSCLC patients treated with anti-PD-1. We recommend FXRhighPD-L1low as a biomarker to predict responsiveness to anti-PD-1 immunotherapy.
©2019 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Immunological / pharmacology
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Antineoplastic Agents, Immunological / therapeutic use
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B7-H1 Antigen / genetics
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B7-H1 Antigen / metabolism*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / etiology*
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Disease Models, Animal
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Female
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Fragile X Mental Retardation Protein / metabolism*
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Gene Expression Regulation, Neoplastic
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Humans
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Immunohistochemistry
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Immunophenotyping
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Lung Neoplasms / drug therapy
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Lung Neoplasms / etiology*
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / metabolism
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Mice
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Molecular Targeted Therapy
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Programmed Cell Death 1 Receptor / metabolism*
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Receptors, Cytoplasmic and Nuclear / genetics*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Tumor Microenvironment / immunology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Immunological
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B7-H1 Antigen
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CD274 protein, human
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Programmed Cell Death 1 Receptor
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Receptors, Cytoplasmic and Nuclear
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farnesoid X-activated receptor
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Fragile X Mental Retardation Protein