Diabetes mellitus type 2 is associated with increased tumor expression of programmed death-ligand 1 (PD-L1) in surgically resected non-small cell lung cancer-A matched case-control study.

ABSTRACT

OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a biomarker for cancer immunotherapy. Diabetes mellitus type-2 is a comorbid disease associated with adverse outcomes in Non-Small Cell Lung Cancer (NSCLC). We aimed to investigate the differences in PD-L1 expression in diabetics. METHODS: A matched case-control cohort of surgically-resected NSCLC was assembled from an early multicenter study (PMID 19152440). PD-L1 immunohistochemistry (Clone 22C3) was graded by a tumor positive score (TPS) system (TPS0 no staining; TPS1 <1%; TPS2 1-49%; TPS3 ≥50%). Variables showing significance at univariate survival analysis were fit in a Cox regression survival model. RESULTS: Diabetics (n=40) and nondiabetics (n=39) showed no differences in age, gender, cancer stage, and follow-up. NSCLCs were more likely PD-L1 positive in diabetics but with tumor positivity <50% (TPS0 7.5 vs. 20.5%, TPS1 35 vs. 25.6%, TPS2 45 vs.23.1%, TPS3 12.5 vs. 30.8%, respectively; P<0.05). In diabetics, squamous cell carcinomas (SCC) and adenocarcinomas were mainly TPS2 (65% vs. 20%) and TPS1 (50% vs. 26%), respectively. Peritumoral inflammation correlated with TPS (r=0.228), a relationship accentuated in diabetics (r=0.377, P<0.05) but diminished and non-significant in nondiabetics (r=0.136, P≥0.05). This association was stronger in SCC (r=0.424). Diabetes was associated with increased tumor recurrence (HR 3.08; 95%CI 1.027-9.23). CONCLUSION: Diabetes is associated with an increase in peritumoral inflammation, PD-L1 positivity, and recurrence in NSCLC, more pronounced in SCC, suggesting the possibility of metabolic reprogramming and upregulation of PD-L1 by inducible pathways.