Purpose: Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine tumor with limited treatment strategies. Programmed death 1 (PD-1) and its ligand (PD-L1), delta-like ligand-3 (DLL-3), and poly ADP-ribose polymerase (PARP) inhibitors have shed light on the treatment of extensive stage-SCLC. However, the expression and prognostic role of PD-L1, DLL-3, and PARP are barely explored in surgically resected limited stage-SCLC (LS-SCLC).
Methods: We retrospectively reviewed 404 SCLC patients from 2011 to 2018 in the First Affiliated Hospital of Xi’an Jiaotong University and collected 43 surgically resected LS-SCLC samples with adequate materials and histological specimens containing abundant tumor cells. Immunohistochemistry staining of PD-L1, DLL-3, and PAPR1 was performed by anti-PD-L1 (22C3/Dako), anti-DLL-3, and anti-PAPR1 antibodies, respectively. Positive expression of PD-L1 was characterized as > 5% tumor cells and/or tumor-infiltrating immune cells expressing PD-L1. The correlation between PD-L1, DLL-3, PARP1, and clinicopathological characteristics of surgically resected LS-SCLC patients was performed by χ² test. The survival curves were calculated by the Kaplan–Meier method and analyzed by the Log rank test and Cox proportional hazards model.
Results and Conclusion: 63.04% patients were positive for PD-L1, 65.12% were positive for DLL-3, and 20.93% were positive for PARP1. DLL-3 was significantly overexpressed in SCLC tissues, compared with matched para-noncancerous tissues. Male, elder than 60 years old, advanced TNM stage, smoking, and positive PD-L1 expression predicted shorter DFS, while patients received adjuvant therapy performed better DFS. Further multivariate analysis revealed that TNM stage (HR=2.51, 95% CI=1.31– 4.78, P =0.005) was an individual prognostic factor for DFS in LS-SCLC. Moreover, advanced TNM stage and positive PD-L1 expression also indicated worse OS, but adjuvant therapy improved OS in LS-SCLC. Multivariate analysis demonstrated that PD-L1 and TNM stage were independent and significant negative predictive factors for OS (HR=2.89, 95% CI=1.21– 6.93, P =0.017; HR=2.49, 95% CI=1.25– 4.94, P =0.009 for PD-L1 and TNM stage, respectively), while adjuvant treatment was an independent positive prognostic factor for OS (HR=0.37, 95% CI=0.17– 0.81, P =0.012).
Keywords: surgically resected LS-SCLC, PD-L1, DLL-3, PARP1