Farnesoid X Receptor Constructs an Immunosuppressive Microenvironment and Sensitizes FXRhighPD-L1low NSCLC to Anti-PD-1 Immunotherapy

Cancer Immunol Res. 2019 Jun;7(6):990-1000. doi: 10.1158/2326-6066.CIR-17-0672. Epub 2019 Apr 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / etiology*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Fragile X Mental Retardation Protein / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Immunophenotyping
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Molecular Targeted Therapy
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Fragile X Mental Retardation Protein