Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy. Issue 10 (14th October 2020)

• Record Type: Journal Article
• Authors: Ebert, Lisa M; Yu, Wenbo; Gargett, Tessa; Toubia, John; Kollis, Paris M; Tea, Melinda N; Ebert, Brenton W; Bardy, Cedric; van den Hurk, Mark; Bonder, Claudine S; Manavis, Jim; Ensbey, Kathleen S; Oksdath Mansilla, Mariana; Scheer, Kaitlin G; Perrin, Sally L; Ormsby, Rebecca J; Poonnoose, Santosh; Koszyca, Barbara; Pitson, Stuart M; Day, Bryan W; Gomez, Guillermo A; Brown, Michael P
• Is Part Of: Clinical & translational immunology. Volume 9:Issue 10(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-14
• Subjects: blood vessels -- fibroblast activation protein -- glioblastoma -- immunotherapy -- scRNAseq -- target antigen; Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1002/cti2.1191
• Languages: English
• ISSNs: 2050-0068

Abstract

Abstract: Objectives: 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. Methods: 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). Results: 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. Conclusion: 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. Abstract : 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.