Whole Exome, RNA Sequencing, and snRNAseq of 181 IDH-wildtype Glioblastoma (GBM) tumors (newly diagnosed and recurrent) to identify genomic and transcriptional features associated with anti-PD(L)1 treatment benefit and acquired resistance. Analysis revealed that the mesenchymal (MES) transcriptional subtype is associated with improved overall survival (OS), while treatment with immune checkpoint blockade (ICB) is linked to the outgrowth of non-MES subclones, suggesting an MES-to-non-MES transition as a common resistance mechanism.
To systematically investigate the genomic features associated with benefit from anti-PD(L)1 in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM), we profiled 181 GBM cases (43 newly diagnosed, 138 recurrent) by whole exome sequencing (WES), targeted panel sequencing, bulk RNA-sequencing (RNA-Seq), and single-nucleus RNA sequenincg (snRNA-Seq). In multivariate survival analysis, baseline tumor transcriptional subtype and presence of their associated genetic lesions emerged as key features predicting overall survival (OS) among newly-diagnosed GBM treated with anti-PD(L)1, with the mesenchymal (MES) subtype associated with improved OS and the proneural subtype associated with poorer OS. Exposure to immune checkpoint blockade (ICB) was associated with outgrowth of subclones harboring lesions associated with non-MES subtype (CDKN2A deletions, PDGFRA gain-of-function mutations), which was not observed in analogous analyses of an external ICB-naive cohort. Our studies support the notion of an MES to non-MES transition as a common trajectory following ICB treatment for GBM.
NCI-phs003614
0342387067_Illumina_P5-Belez_P7-Yoxen