METB-01. The integrated analysis of alternative splicing reveals therapeutic targets in pediatric brain tumor

Alternative splicing derived neoantigens can be served as promising immunotherapeutic targets for tumor. However, little is known about the AS milieu in Pediatric glioma, including diffuse midline glioma (DMG), pediatric high grade glioma (pHGG) and medulloblastoma (MB). We performed integrated analysis of alternative splicing using bulk RNA-seq and single cell RNA-seq datasets of pediatric brain tumor specimens, including 9 DMG, 25 pHGG and 19 MB cases. We also re-analyzed RNA-sequencing data from non-malignant human brain tissues. We reconstructed the landscape of AS in Pediatric glioma and contrasted that to observed isoforms in non-malignant brain. We found that AS score can be used to stratify the MB patients samples, and high AS score was significantly associated with worse survival in MB. We identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies in DMG, pHGG and MB. We also identified novel splicing events derived neoantigens in DMG, pHGG and MB respectively, which are potential immunotherapy targets. We found MB specific isoforms of transforming growth factor beta (TGFβ) signaling pathway genes which are expressed exclusively by MB tumor cells. Our studies shed light on the effect of immunotherapy on AS and identify novel targets for emerging immunotherapies in pediatric brain tumor.