非小细胞肺癌中与PD-L1和PD-L2表达相关的基因

背景程序性细胞死亡配体1(programmed cell death ligand-1,PD-L1)和配体2(programmed cell death ligand-2,PD-L2)与程序性细胞死亡受体1(programmed cell death protein-1,PD-1)的相互作用是一个介导免疫逃逸的免疫抑制检查点,因此是癌症中基于阻滞的免疫治疗的重要靶点。在非小细胞肺癌(nonsmall-celllungcancer,NSCLC)中,有必要对PD-1检查点阻滞反应生物学进行深入了解,并确定生物标志物以预测其对免疫疗法的临床反应。在本研究中,我们系统描述了NSCLC中PD-L1和PD-L2表达相关基因。方法我们进行了回顾性比较分析,来确定NSCLC中PD-L1和PD-L2 mRNA表达相关基因。为此,我们考察了肿瘤细胞系百科全书(Cancer Cell Line Encyclopedia,CCLE)数据库中肺–非小细胞(lung non-small-cell,Lung_NSC)和癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中肺腺癌(lung adenocarcinoma,LUAD)和鳞状细胞癌(lung squamous cell carcinoma,LUSC)的可用数据集。结果通过对CCLE数据集Lung_NSC的分析确定了PD-L1和PD-L2之间的表达相关性。此外,我们发现了489个基因与PD-L1相关、191个基因与PD-L2相关,以及111个基因与二者均有表达相关性。在TCGA数据集LUAD和LUSC中对PD-L1和PD-L2也进行了表达相关研究。在LUAD中,我们发现了257个基因与PD-L1相关、914个基因与PD-L2相关以及211个基因与二者均有表达相关性。在LUSC中,我们发现了26个基因与PD-L1相关、326个基因与PD-L2相关以及13个基因与二者均有表达相关性。只有少数基因表达在CCLE和TCGA数据集中均表现为与PD-L1和PD-L2相关。涉及干扰素信号转导基因的表达尤其与Lung_NSC中的PD-L1、LUSC中的PD-L2以及LUAD中的PD-L1和PD-L2的表达相关基因汇聚。在LUSC,PD-L1的表达,以及PD-L2的表达(相比之下相关程度较小)与染色体9p24区的基因相关,表明染色体9p24拓扑相关结构域是LUSC中PD-L1表达特别重要的驱动力。对PD-L1和PD-L2的受体PD-1、分化群80(cluster of differentiation,CD80)和排斥导向分子B(repulsive guidance molecule B,RGMB)的表达相关分析表明,在LUAD中PD-1和CD80表达与PD-L1和PD-L2均相关。在LUSC中CD80表达与PD-L2相关。结论我们提出了与NSCLC中PD-L1和PD-L2 mRNA表达相关的基因特征,这可能对于了解PD-1检查点阻滞反应生物学和开发基于基因特征的生物标志物以预测免疫疗法的临床反应具有重要意义。

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.