Defining intrinsic and acquired mechanisms of immune checkpoint blockade resistance in glioblastoma
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, and bulk RNA-sequencing (RNA-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... (for more see dbGaP study page.)