High farnesoid X receptor expression predicts favorable clinical outcomes in PD‑L1 low/negative non‑small cell lung cancer patients receiving anti‑PD‑1‑based chemo‑immunotherapy.

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‑L1 ^low/negative patients who will benefit from immunotherapy. It was previously reported that farnesoid X receptor (FXR) downregulated PD‑L1 expression in NSCLC, and that FXR ^high PD‑L1 ^low mouse Lewis lung carcinoma tumors showed an increased susceptibility to PD‑1 blockade compared with mock tumors. At present, whether the FXR ^high PD‑L1 ^low 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‑L1 ^low patients. Cox multivariate analysis revealed that high FXR expression was an independent predictor for PFS and OS in PD‑L1 ^low patients. Tumor microenvironment evaluation revealed a statistically significant decrease of infiltrating CD8 ⁺ T cells in FXR ^high specimens with NSCLC. Overall, the present study proposed an FXR ^high PD‑L1 ^low signature as a candidate predictor of response to anti‑PD‑1‑based chemo‑immunotherapy in PD‑L1 ^low/negative patients with NSCLC, providing evidence that could be used to broaden the patients benefitting from immunotherapy.