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

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 FXR^highPD-L1^low patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXR^highPD-L1^low NSCLC cell lines, effector function and proliferation of CD8⁺ T cell <i>in vitro</i> are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXR^highPD-L1^low subtype in which FXR suppresses tumor-infiltrating immune cells. Anti-PD-1 therapy was effective against FXR^highPD-L1^low mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXR^highPD-L1^low NSCLC subtype and provide translational insights into therapeutic response in PD-L1^low NSCLC patients treated with anti-PD-1. We recommend FXR^highPD-L1^low as a biomarker to predict responsiveness to anti-PD-1 immunotherapy.