Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.
Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.
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DOI：
10.1002/cti2.1191
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发表时间：
2020
影响因子：
5.8
通讯作者：
Brown MP
中科院分区：
文献类型：
--
作者：
Ebert LM;Yu W;Gargett T;Toubia J;Kollis PM;Tea MN;Ebert BW;Bardy C;van den Hurk M;Bonder CS;Manavis J;Ensbey KS;Oksdath Mansilla M;Scheer KG;Perrin SL;Ormsby RJ;Poonnoose S;Koszyca B;Pitson SM;Day BW;Gomez GA;Brown MP
嵌合抗原受体(CAR) - T细胞等靶向免疫疗法正在成为胶质母细胞瘤的有吸引力的治疗选择，但依赖于鉴定合适的肿瘤抗原。我们通过对人类样本的详细表达研究，验证了一种新的胶质母细胞瘤靶抗原，成纤维细胞激活蛋白（FAP）。利用免疫染色对胶质母细胞瘤和正常组织进行评估，并对已发表的转录组数据集进行分析。用流式细胞术将神经胶质瘤神经干（GNS）细胞的短期培养与健康星形胶质细胞和神经元的培养进行比较。胶质母细胞瘤组织分离，并通过高参数流式细胞术和单细胞转录组学（scRNAseq）进行分析。与正常大脑相比，FAP在很大比例的胶质母细胞瘤组织中在基因和蛋白水平上过表达，最高表达水平与较差的预后相关。FAP在一些儿童脑癌中也过表达。FAP在培养的GNS细胞中普遍表达，但在正常神经元和星形胶质细胞中不表达。在胶质母细胞瘤组织中，FAP在血管周围表达最强。事实上，几乎每个肿瘤血管都有FAP的表达，而正常组织血管和培养的内皮细胞（ECs）则缺乏表达。分离肿瘤的单细胞分析有助于详细描述胶质母细胞瘤微环境的主要细胞成分，并揭示血管定位的FAP是由于内皮细胞和周细胞上的表达。成纤维细胞激活蛋白在胶质母细胞瘤内的多种细胞类型中表达，突出表明它是一种理想的免疫治疗抗原，可以靶向破坏肿瘤细胞及其支持血管网络。对成纤维细胞活化蛋白（FAP）表达模式的详细分析表明，FAP是胶质母细胞瘤免疫治疗的重要新靶抗原。组织切片的免疫染色、流式细胞术和单细胞RNA测序显示，FAP不仅在胶质母细胞瘤肿瘤细胞中广泛表达，而且在肿瘤微环境中的内皮细胞和周细胞中也广泛表达。
Targeted immunotherapies such as chimeric antigen receptor (CAR)‐T cells are emerging as attractive treatment options for glioblastoma, but rely on identification of a suitable tumor antigen. We validated a new target antigen for glioblastoma, fibroblast activation protein (FAP), by undertaking a detailed expression study of human samples. Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datasets. Short‐term cultures of glioma neural stem (GNS) cells were compared to cultures of healthy astrocytes and neurons using flow cytometry. Glioblastoma tissues were dissociated and analysed by high‐parameter flow cytometry and single‐cell transcriptomics (scRNAseq). Compared to normal brain, FAP was overexpressed at the gene and protein level in a large percentage of glioblastoma tissues, with highest levels of expression associated with poorer prognosis. FAP was also overexpressed in several paediatric brain cancers. FAP was commonly expressed by cultured GNS cells but absent from normal neurons and astrocytes. Within glioblastoma tissues, the strongest expression of FAP was around blood vessels. In fact, almost every tumor vessel was highlighted by FAP expression, whereas normal tissue vessels and cultured endothelial cells (ECs) lacked expression. Single‐cell analyses of dissociated tumors facilitated a detailed characterisation of the main cellular components of the glioblastoma microenvironment and revealed that vessel‐localised FAP is because of expression on both ECs and pericytes. Fibroblast activation protein is expressed by multiple cell types within glioblastoma, highlighting it as an ideal immunotherapy antigen to target destruction of both tumor cells and their supporting vascular network. This detailed analysis of the expression patterns of fibroblast activation protein (FAP) reveals it to be an important new target antigen for immunotherapy of glioblastoma. Immunostaining of tissue sections, flow cytometry and single‐cell RNA sequencing reveal broad expression of FAP by not only glioblastoma tumour cells but also endothelial cells and pericytes within the tumour microenvironment.
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影响因子：
6
作者：
D'Souza, Rochelle C. J.;Offenhauser, Carolin;Day, Bryan W.
通讯作者：
Day, Bryan W.
影响因子：
3.4
作者：
Annunziata, Christina M;Kohn, Elise C;LoRusso, Patricia;Houston, Nicole D;Coleman, Robert L;Buzoianu, Manuela;Robbie, Gabriel;Lechleider, Robert
通讯作者：
Lechleider, Robert
影响因子：
2.6
作者：
Fedchenko N;Reifenrath J
通讯作者：
Reifenrath J
影响因子：
11
作者：
Bardy, C.;van den Hurk, M.;Kakaradov, B.;Erwin, J. A.;Jaeger, B. N.;Hernandez, R. V.;Eames, T.;Paucar, A. A.;Gorris, M.;Marchand, C.;Jappelli, R.;Barron, J.;Bryant, A. K.;Kellogg, M.;Lasken, R. S.;Rutten, B. P. F.;Steinbusch, H. W. M.;Yeo, G. W.;Gage, F. H.
通讯作者：
Gage, F. H.
影响因子：
--
作者：
Boyer, Leah F;Campbell, Benjamin;Gage, Fred H
通讯作者：
Gage, Fred H