Single cell RNAseq-based proteogenomics identifies glioblastoma-specific transposable elements encoding HLA-presented peptides

We developed a transposable element (TE)-centered proteogenomic pipeline that combines single cell transcriptomics on tumors from glioblastoma (GBM) patients, bulk RNAseq samples from tumor and healthy tissue cohorts, and immunopeptidomics. We thus identified 370 HLA-I-bound peptides encoded by TEs differentially expressed in GBM. Some of the peptides are encoded by repeat sequences from intact open reading frames (ORFs) present in up to several hundred TEs from recent LINE-1, LTR and SVA subfamilies. Other HLA-I-bound peptides are encoded by unique copies of TEs from old subfamilies that are expressed recurrently in GBM tumors and not expressed, or very infrequently and at low levels, in healthy tissues (including brain). These peptide-coding, GBM-specific, highly recurrent TEs represent potential tumor-specific targets for cancer immunotherapies.