PD-L1 expression-related PI3K pathway correlates with immunotherapy efficacy in gastric cancer

BACKGROUND: The programed death ligand-1 combined positive score (PD-L1 CPS), the only FDA-approved biomarker for immune checkpoint inhibitor therapy in gastric cancer (GC) patients, is an important but imperfect predictive biomarker. The molecular characteristics of tumors that influence the PD-L1 CPS are largely unknown and would be helpful for screening patients who would benefit from immunotherapy. METHODS: PD-L1 immunohistochemistry (IHC) and targeted next-generation sequencing techniques were used to compare genomic alterations in 492 GC patients in two groups (PD-L1 CPS ⩾ 1, positive; CPS < 1, negative). Screened PD-L1 expression-related factors were analyzed for immunotherapy efficacy in three distinct GC cohorts from public databases. RESULTS: Positive PD-L1 expression occurred in 40% of GC patients and was associated with a higher proportion of phosphatidylinositol 3-kinase (PI3K), SWItch/Sucrose NonFermentable (SWI/SNF), lysine demethylase (KDM), and DNA (cytosine-5)-methyltransferase (DNMT) (all p < 0.01), pathway alterations. Compared to wild-type GC patients, those with PI3K pathway alterations had a higher response rate (p = 0.002) and durable clinical benefit rate with immunotherapy (p = 0.023, p = 0.038) as well as longer progression-free survival (p = 0.084, p = 0.0076) and overall survival (p = 0.2, p = 0.037) with immunotherapy. CONCLUSION: This study revealed PD-L1 expression-related factors in the tumor genome in a GC cohort. Alterations in the PI3K pathway associated with PD-L1 positivity were shown to be associated with better immunotherapy efficacy in three distinct GC cohorts from public databases. Our results provide a potential avenue for patient selection and rational immune combination development for GC patients.