High farnesoid X receptor expression predicts favorable clinical outcomes in PD-L1low/negative non-small cell lung cancer patients receiving anti-PD-1-based chemo-immunotherapy

Abstract

Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-directed immunotherapy has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, predictive biomarkers are still lacking, particularly in identifying PD-L1low/negative patients who will benefit from immunotherapy. It was previously reported that farnesoid X receptor (FXR) downregulated PD-L1 expression in NSCLC, and that FXRhighPD-L1low mouse Lewis lung carcinoma tumors showed an increased susceptibility to PD-1 blockade compared with mock tumors. At present, whether the FXRhighPD-L1low phenotype predicts clinical response to immunotherapy in patients with NSCLC remains unclear. Herein, a retrospective study was conducted to examine the expression levels of FXR, PD-L1 and CD8+ T cells by immunohistochemistry in a cohort of 149 patients with NSCLC receiving anti-PD-1-based chemo-immunotherapy. The results revealed that high FXR and PD-L1 expression levels were associated with higher objective response rates (ORR) in all patients. High PD-L1 expression also indicated superior progression-free survival (PFS). Interestingly, an inverse correlation was identified between FXR and PD-L1 expression in specimens with NSCLC. Subgroup analysis revealed that high FXR expression was associated with a higher ORR, as well as longer PFS and overall survival (OS) in PD-L1low patients. Cox multivariate analysis revealed that high FXR expression was an independent predictor for PFS and OS in PD-L1low patients. Tumor microenvironment evaluation revealed a statistically significant decrease of infiltrating CD8+ T cells in FXRhigh specimens with NSCLC. Overall, the present study proposed an FXRhighPD-L1low signature as a candidate predictor of response to anti-PD-1-based chemo-immunotherapy in PD-L1low/negative patients with NSCLC, providing evidence that could be used to broaden the patients benefitting from immunotherapy.