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Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.

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.

SUBMITTER: Ebert LM

PROVIDER: S-EPMC7557106 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.

Ebert Lisa M LM Yu Wenbo W Gargett Tessa T Toubia John J Kollis Paris M PM Tea Melinda N MN Ebert Brenton W BW Bardy Cedric C van den Hurk Mark M Bonder Claudine S CS Manavis Jim J Ensbey Kathleen S KS Oksdath Mansilla Mariana M Scheer Kaitlin G KG Perrin Sally L SL Ormsby Rebecca J RJ Poonnoose Santosh S Koszyca Barbara B Pitson Stuart M SM Day Bryan W BW Gomez Guillermo A GA Brown Michael P MP

Clinical & translational immunology 20201014 10

<h4>Objectives</h4>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.<h4>Methods</h4>Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datase ...[more]

PMID: 33082953

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Project description:BackgroundCancer-associated fibroblasts (CAFs) can strongly modulate the response to therapy of malignant tumor cells, facilitating their continuous proliferation and invading behaviors. In this context, several efforts were made in identifying the fibroblast activation protein (FAP) as a CAF recognizer and in designing FAP-specific PET radiotracers (as 68Ga-FAPI) along with FAP-specific therapeutic radioligands. Herein, we review different clinical studies using the various FAP-specific radioligands as novel theranostic agents in a wide range of oncologic and nononcologic indications.MethodsA comprehensive systematic search was conducted on the PubMed and Scopus databases to find relevant published articles concerning the FAP-specific PET imaging as well as the FAP-specific radionuclide therapy in patients with oncologic and nononcologic indications. The enrolled studies were dichotomized into oncologic and nononcologic categories, and the required data were extracted by precisely reviewing the whole text of each eligible study. A meta-analysis was also performed comparing the detection rates of 68Ga-FAPI vs. 18F-FDG PET/CT using odds ratio (OR) and risk difference as outcome measures.ResultsOf the initial 364 relevant papers, 49 eligible articles (1479 patients) and 55 case reports were enrolled in our systematic review. These studies observed high radiolabeled FAPI avidity as early as 10 minutes after administration in primary sites of various malignant tumors. Based on the meta-analysis which was done on the reported detection rates of the 68Ga-FAPI and 18F-FDG PET/CT scans, the highest OR belonged to the primary lesion detection rate of gastrointestinal tumors (OR = 32.079, 95% CI: 4.001-257.212; p = 0.001) with low heterogeneity (I2 = 0%). The corresponding value of the nodal metastases belonged to hepatobiliary tumors (OR = 11.609, 95% CI: 1.888-71.365; p = 0.008) with low heterogeneity (I2 = 0%). For distant metastases, the highest estimated OR belonged to nasopharyngeal carcinomas (OR = 77.451, 95% CI: 7.323-819.201; p < 0.001) with low heterogeneity (I2 = 0%).ConclusionsThe outperformance of 68Ga-FAPI PET/CT over 18F-FDG PET/CT in identifying certain primary tumors as well as in detecting their metastatic lesions may open indications for evaluation of cases with inconclusive 18F-FDG PET/CT findings. What needs to be emphasized is that the false-positive results might be problematic and must be taken into account in 68Ga-FAPI PET/CT interpretation. More clarification on the role of FAPI radioligands in oncologic imaging, radionuclide therapy, and radiotherapy treatment planning is therefore required.

Dataset Information

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.

Publications

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.

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