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.
Highlights
Non–small cell lung cancer (NSCLC), which constitutes about 85% of all lung cancers, remains a leading cause of cancer mortality worldwide [1]
We found that the proportion of FXRhighPD-L1low tumors was up to 42.6% in all NSCLC samples
We found an inverse correlation between farnesoid X receptor (FXR) and PD-L1 expression in a cohort of 408 samples from patients with NSCLC
Summary
Non–small cell lung cancer (NSCLC), which constitutes about 85% of all lung cancers, remains a leading cause of cancer mortality worldwide [1]. The identification of tumor oncogenic gene alterations has transformed the management of NSCLC, leading to responses in selected patients treated with matched tyrosine-kinase inhibitors [2]. The tumor microenvironment (TME) emerged as a target for anticancer therapy development, because the interaction between tumor cells and stromal tumor–promoting immune cells plays a role in. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
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