Abstract
Glioblastoma (GBM) is the most common and devastating malignant brain tumor in adults. The mortality rate is very high despite different treatments. New therapeutic targets are therefore highly needed. Cell-surface proteins represent attractive targets due to their accessibility, their involvement in essential signaling pathways, and their dysregulated expression in cancer. Moreover, they are potential targets for CAR-based immunotherapy or mRNA vaccine strategies. In this context, we investigated the GBM-associated surfaceome by comparing it to astrocytes cell line surfaceome to identify new specific targets for GBM. For this purpose, biotinylation of cell surface proteins has been carried out in GBM and astrocytes cell lines. Biotinylated proteins were purified on streptavidin beads and analyzed by shotgun proteomics. Cell surface proteins were identified with Cell Surface Proteins Atlas (CSPA) and Gene Ontology enrichment. Among all the surface proteins identified in the different cell lines we have confirmed the expression of 66 of these in patient’s glioblastoma using spatial proteomic guided by MALDI-mass spectrometry. Moreover, 87 surface proteins overexpressed or exclusive in GBM cell lines have been identified. Among these, we found 11 specific potential targets for GBM including 5 mutated proteins such as RELL1, CYBA, EGFR, and MHC I proteins. Matching with drugs and clinical trials databases revealed that 7 proteins were druggable and under evaluation, 3 proteins have no known drug interaction yet and none of them are the mutated form of the identified proteins. Taken together, we discovered potential targets for immune therapy strategies in GBM.
Highlights
Glioblastoma represents the main malignant primary brain tumor with an incidence of 3.22 per 100,000 population [1]
We compared the surfaceome of two different human glioblastoma cell lines, U87 and NCH82, with a human astrocyte cell line
Surface proteins were identified by cross-checking the total list of heatmap proteins with the lists of surface proteins provided by the cell surface protein atlas (CSPA) [13] and the list of predicted surfaceome proteins [14]
Summary
Glioblastoma represents the main malignant primary brain tumor with an incidence of 3.22 per 100,000 population [1]. Very few GBM-specific antigens have been identified so far and they show a very limited potential as targets for immunotherapy. It is possible to compare new surfaceome proteomic dataset provided experimentally to CSPA database and from mutated peptides from XMan v.2 database [15] In this context, we compared astrocytoma GBM cell lines to normal astrocytes cell line. We could identify 11 specific potential targets for GBM including 5 mutated proteins (PLAUR, ITGB3, and MHC I proteins). The specificity of these proteins to GBM has been validated using the human protein atlas and a cohort of 50 GBM patients
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