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 importa...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 cel展开更多
The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is part...The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is partially due to less understanding of the biological regulation of PD-L1.Here,we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation.In PD-L1 and PD-L2 highly expressed cancer cells,a new TAD(topologically associating domain)(chr9:5,400,000-5,600,000)around CD274 and CD273 was discovered,which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2.The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1.After transcription,the PD-L1 is tightly regulated by mi RNAs and RNA-binding proteins via the long 3’UTR.At translational level,PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination.In addition,PD-L1 can be secreted via exosome to systematically inhibit immune response.Therefore,fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.展开更多
背景与目的:程序性死亡[蛋白]-1(programmed death-1,PD-1)单抗免疫治疗在头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)中的作用愈发重要,然而目前具有响应率低、缺乏预测性生物标志物的问题。本研究旨在确定程序性...背景与目的:程序性死亡[蛋白]-1(programmed death-1,PD-1)单抗免疫治疗在头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)中的作用愈发重要,然而目前具有响应率低、缺乏预测性生物标志物的问题。本研究旨在确定程序性死亡[蛋白]配体-2(programmed death ligand-2,PD-L2)能否作为预测HNSCC中PD-1单抗免疫治疗获益情况的生物标志物。方法:收集50例接受PD-1单克隆抗体免疫治疗的中晚期HNSCC的组织标本及临床数据,采用免疫组织化学染色法分析程序性死亡[蛋白]配体-1(programmed death ligand-1,PD-L1)、PD-L2表达量,采用SPSS 26.0软件根据基本临床特征、PD-L1与PD-L2表达量分组统计并进行Kaplan-Meier生存分析,采用GraphPad Prism软件绘制生存曲线。结果:PD-L2在HNSCC患者中阳性表达率较高,有超过80%的患者肿瘤组织可检出PD-L2表达;PD-L2的表达量显著影响免疫治疗结局,PD-L2高表达的患者平均生存期为18.8(16.0~21.7)个月,而PD-L2低表达的患者平均生存期为11.0(9.1~12.8)个月,差异有统计学意义(P<0.05)。结论:PD-L2可作为评估HNSCC中PD-1单克隆抗体免疫治疗获益的生物标志物。展开更多
基金This study was supported by Familien Erichsens Familiefond.TVL and DH are supported by Ph.D.fellowships from the Faculty of Health,Aarhus University,Denmark
文摘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 cel
基金supported by the National Natural Science Foundation of China(3197061631770935+2 种基金81873531and 82070505)the Distinguished Professorship Program of Jiangsu Province to Yihui Fan,the Distinguished Professorship Program of Jiangsu Province to Renfang Mao,The National Undergraduate Training Programs for Innovation(202010304109Y,China)。
文摘The immune checkpoint blockade(ICB)targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers.However,the low response rate and frequently observed severe side effects limit its broad benefits.It is partially due to less understanding of the biological regulation of PD-L1.Here,we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation.In PD-L1 and PD-L2 highly expressed cancer cells,a new TAD(topologically associating domain)(chr9:5,400,000-5,600,000)around CD274 and CD273 was discovered,which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2.The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1.After transcription,the PD-L1 is tightly regulated by mi RNAs and RNA-binding proteins via the long 3’UTR.At translational level,PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination.In addition,PD-L1 can be secreted via exosome to systematically inhibit immune response.Therefore,fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.
文摘背景与目的:程序性死亡[蛋白]-1(programmed death-1,PD-1)单抗免疫治疗在头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)中的作用愈发重要,然而目前具有响应率低、缺乏预测性生物标志物的问题。本研究旨在确定程序性死亡[蛋白]配体-2(programmed death ligand-2,PD-L2)能否作为预测HNSCC中PD-1单抗免疫治疗获益情况的生物标志物。方法:收集50例接受PD-1单克隆抗体免疫治疗的中晚期HNSCC的组织标本及临床数据,采用免疫组织化学染色法分析程序性死亡[蛋白]配体-1(programmed death ligand-1,PD-L1)、PD-L2表达量,采用SPSS 26.0软件根据基本临床特征、PD-L1与PD-L2表达量分组统计并进行Kaplan-Meier生存分析,采用GraphPad Prism软件绘制生存曲线。结果:PD-L2在HNSCC患者中阳性表达率较高,有超过80%的患者肿瘤组织可检出PD-L2表达;PD-L2的表达量显著影响免疫治疗结局,PD-L2高表达的患者平均生存期为18.8(16.0~21.7)个月,而PD-L2低表达的患者平均生存期为11.0(9.1~12.8)个月,差异有统计学意义(P<0.05)。结论:PD-L2可作为评估HNSCC中PD-1单克隆抗体免疫治疗获益的生物标志物。
