PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer

Background:Programmed cell death ligand-1(PD-L1)and ligand-2(PD-L2)interaction with programmed cell death protein-1(PD-1)represent an immune-inhibiting checkpoint mediating immune evasion and is,accordingly,an important target for blockade-based immunotherapy in cancer.In non-small-cell lung cancer(NSCLC),improved understanding of PD-1 checkpoint blockade-responsive biology and identification of biomarkers for prediction of a clinical response to immunotherapy is warranted.Thus,in the present study,we systematically described PD-L1 and PD-L2 expression correlated genes in NSCLC.Methods:We performed comparative retrospective analyses to identify PD-L1 and PD-L2 mRNA expression corre-lated genes in NSCLC.For this,we examined available datasets from the cancer cell line encyclopedia(CCLE)project lung non-small-cell(Lung_NSC)and the cancer genome atlas(TCGA)projects lung adenocarcinoma(LUAD)and squamous cell carcinoma(LUSC).Results:Analysis of the CCLE dataset Lung_NSC identified expression correlation between PD-L1 and PD-L2.Moreo-ver,we identified expression correlation between 489 genes and PD-L1,191 genes and PD-L2,and 111 genes for both.PD-L1 and PD-L2 also expression correlated in TCGA datasets LUAD and LUSC.In LUAD,we identified expression corre-lation between 257 genes and PD-L1,914 genes and PD-L2,and 211 genes for both.In LUSC,we identified expression correlation between 26 genes and PD-L1,326 genes and PD-L2,and 13 genes for both.Only a few genes expression correlated with PD-L1 and PD-L2 across the CCLE and TCGA datasets.Expression of Interferon signaling-involved genes converged in particular with the expression correlated genes for PD-L1 in Lung_NSC,for PD-L2 in LUSC,and for both PD-L1 and PD-L2 in LUAD.In LUSC,PD-L1,and to a lesser extent PD-L2,expression correlated with chromosome 9p24 localized genes,indicating a chromosome 9p24 topologically associated domain as an important driver of in particu-lar LUSC PD-L1 expression.Expression correlation analyses of the PD-L1 and PD-L2 receptors programmed cell death protein-1(PD-1),Cluster of differentiation 80(CD80),and Repulsive guidance molecule B(RGMB)showed that PD-1 and CD80 expression correlated with both PD-L1 and PD-L2 in LUAD.CD80 expression correlated with PD-L2 in LUSC.Conclusions:We present gene signatures associated with PD-L1 and PD-L2 mRNA expression in NSCLC which could possess importance in relation to understand PD-1 checkpoint blockade-responsive biology and development of gene signature based biomarkers for predicting clinical responses to immunotherapy.