Evaluating the significance of combining PD-L1 and TILs as biomarkers in non-small cell lung cancer patients treated with immunotherapy: a systematic review

In advanced non-small cell lung cancer (NSCLC), programmed death-ligand 1 (PD-L1) expression is a well-established but suboptimal biomarker for predicting response to immune checkpoint inhibitors (ICIs). Tumor-infiltrating lymphocytes (TILs), particularly CD8+ subsets, have demonstrated potential as complementary biomarker. Despite existing data on each biomarker individually, the combined effect is not fully understood. A systematic search of Ovid/Medline, Embase, and Web of Science identified studies on CD8+ TILs and PD-L1 in NSCLC patients treated with ICIs. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR) and durable clinical benefit (DCB). Study quality was assessed using the Newcastle-Ottawa Scale. Thirteen studies (2490 patients) were included. PD-L1 expression was associated with longer PFS in 6 of 8 studies (HR: 0.67, 95% CI: 0.49-0.90) but did not significantly correlate with OS. TILs alone showed no significant predictive value for PFS or OS. However, combining both biomarkers provided the strongest predictive value for PFS (HR: 0.39, 95% CI: 0.27-0.57) and OS (HR: 0.42, 95% CI: 0.31-0.56). Combining PD-L1 and TILs may more effectively predict PFS and OS than either biomarker alone, though their clinical application remains complex.