BTLA Expression in Stage I–III Non–Small-Cell Lung Cancer and Its Correlation with PD-1/PD-L1 and Clinical Outcomes

BACKGROUND: B and T lymphocyte attenuator (BTLA) is a novel immune checkpoint with an unclear role in non–small-cell lung cancer (NSCLC). In contrast, the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint is a potentially curative immunotherapy target in NSCLC. Our study investigated BTLA expression and its relationship with PD-1/PD-L1, tumor-infiltrating lymphocytes (TILs), and clinicopathological features. METHODS: The protein expressions of BTLA, PD-1, and PD-L1 were evaluated by immunohistochemistry (IHC) and TIL abundance was scored in paraffin-embedded tissues from surgically resected specimens from 87 patients with stage I–III NSCLC. RESULTS: BTLA was expressed in tumor cells in 35 patients with NSCLC (40.2%). In addition, 42 patients (48.3%) were positive for PD-1 in TILs and 31 (35.6%) were positive for PD-L1 in tumor cells. BTLA was overexpressed in patients with lymphatic invasion (P=0.045) and an advanced tumor stage (P=0.034). High expression of BTLA was positively correlated with a high level of PD-L1 (P=0.011). Patients with positive BTLA expression had a shorter relapse-free survival (RFS) than those with negative BTLA expression (P=0.029). Moreover, patients negative for both BTLA and PD-L1 had a longer RFS than patients who were positive for BTLA or PD-L1 or for both checkpoints (P=0.012). The same pattern was shown for overall survival (P=0.031). CONCLUSION: High BTLA expression may predict poor prognosis in patients with NSCLC and may represent a new immunotherapy target.