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 correlated 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. Moreover, 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 correlation 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 particular 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 bl