CA9-Related Acidic Microenvironment Mediates CD8+ T Cell Related Immunosuppression in Pancreatic Cancer.
CA9-Related Acidic Microenvironment Mediates CD8+ T Cell Related Immunosuppression in Pancreatic Cancer.
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CA9相关酸性微环境介导胰腺癌中CD8 T细胞相关免疫抑制
DOI：
10.3389/fonc.2021.832315
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发表时间：
2021
影响因子：
4.7
通讯作者：
Peng Y
中科院分区：
文献类型：
--
作者：
Yin L;Lu Y;Cao C;Lu Z;Wei J;Zhu X;Chen J;Guo F;Tu M;Xi C;Zhang K;Wu J;Gao W;Jiang K;Miao Y;Li Q;Peng Y
目的本研究旨在整合胰腺癌TCGA、GEO和单细胞RNA测序（scRNA-seq）数据集，通过生物信息学方法、体外和体内实验，探索胰腺癌免疫微环境的潜在预后标志物和潜在机制。方法下载胰腺癌TCGA、GEO（GSE 131050）、单细胞测序（PAAD_CRA001160）数据集的表达数据和临床病理数据。我们使用R/Bioconductor edgeR进行差异表达分析。利用QuantiterProfiler对差异表达基因进行GO富集分析。应用CIBERSORT软件对胰腺癌mRNA表达数据进行再分析。使用CellRanger、RunPCA、FindNeighbors、FindClusters、RunTSNE和RunUMAP对单细胞测序数据集进行预处理、细胞聚类和表达谱分析。我们分析了有或没有CA9抑制剂SLC-0111的细胞内pH。使用人胰腺癌细胞系和健康个体来源的PBMC的间接共培养模型来确定CA9相关酸性微环境对CD8 + T细胞的影响。结果TCGA胰腺癌转录组测序数据的CIBERSORT分析显示，在22种免疫微环境成分中，CD8 + T细胞浸润与胰腺癌患者预后显著相关。根据CD8 + T细胞浸润水平分组的TCGA数据的差异表达分析表明，碳酸酐酶9（CA9）的表达最显著，并且生存分析表明CA9与胰腺癌的总体生存相关。TCGA数据和GEO数据集GSE 131050表达相关性分析提示CA9和CD8表达密切相关。胰腺癌单细胞测序数据集PAAD_CRA001160分析结果显示，CA9主要在胰腺癌细胞簇中表达，单细胞数据集中癌细胞亚群CA9的表达与CD8 + T细胞浸润相关。结论胰腺癌细胞可能通过CA9抑制CD8 + T细胞的浸润。对其相关机制的深入探讨可为探索胰腺癌的免疫逃逸途径和免疫靶向治疗提供新的视角。
Purpose This study aims to integrate pancreatic cancer TCGA, GEO, and single-cell RNA-sequencing (scRNA-seq) datasets, and explore the potential prognostic markers and underlying mechanisms of the immune microenvironment of pancreatic cancer through bioinformatics methods, in vitro and in vivo assays. Methods Expression data and clinicopathological data of pancreatic cancer TCGA, GEO (GSE131050), single cell sequencing (PAAD_CRA001160) dataset were downloaded. We used R/Bioconductor edgeR for differential expression analysis. ClusterProfiler was utilized to perform GO enrichment analysis on differentially expressed genes. The online software CIBERSORT was used to reanalyze the mRNA expression data of pancreatic cancer. CellRanger, RunPCA, FindNeighbors, FindClusters, RunTSNE and RunUMAP were used to perform preprocessing, cell clustering and expression profile analysis on single-cell sequencing data sets. We analyzed intracellular pH with or without CA9 inhibitor SLC-0111. Indirect co-culture model of human pancreatic cancer cell lines and healthy individual-derived PBMCs were used to determine the effect of CA9-related Acidic Microenvironment on CD8+ T cells. Results The CIBERSORT analysis of TCGA pancreatic cancer transcriptome sequencing data showed that among the 22 immune microenvironment components, CD8+ T cell infiltration was significantly correlated with the prognosis of pancreatic cancer patients. The differential expression analysis of the TCGA data grouped by the level of CD8+ T cell infiltration indicates that the expression of carbonic anhydrase 9 (CA9) is the most significant, and the survival analysis suggests that CA9 is associated with the overall survival of pancreatic cancer. TCGA data and GEO data set GSE131050 expression correlation analysis suggests that CA9 and CD8 expression are closely related. Pancreatic cancer single-cell sequencing data set PAAD_CRA001160 analysis results show that CA9 is mainly expressed in pancreatic cancer cell clusters, and the expression of the cancer cell subgroup CA9 in the single-cell data set is correlated with CD8+ T cell infiltration. Conclusion Pancreatic cancer cells may inhibit the infiltration of CD8+ T cells through CA9. Further exploration of its related mechanisms can be used to explore the immune escape pathway of pancreatic cancer and provides new perspectives immune targeted therapy.
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影响因子：
2.8
作者：
Li, Yuji;Dong, Ming;Huang, Longping
通讯作者：
Huang, Longping
影响因子：
29.4
作者：
Ene-Obong A;Clear AJ;Watt J;Wang J;Fatah R;Riches JC;Marshall JF;Chin-Aleong J;Chelala C;Gribben JG;Ramsay AG;Kocher HM
通讯作者：
Kocher HM
影响因子：
10.1
作者：
Stromnes IM;Hulbert A;Pierce RH;Greenberg PD;Hingorani SR
通讯作者：
Hingorani SR
影响因子：
6.4
作者：
Baniak, Nicholas;Flood, Trevor A.;Hirsch, Michelle S.
通讯作者：
Hirsch, Michelle S.
影响因子：
6.6
作者：
Kirby, Marie K.;Ramaker, Ryne C.;Myers, Richard M.
通讯作者：
Myers, Richard M.