The evolution of alternative splicing in glioblastoma under therapy

Lin Wang,Hideho Okada,Takahide Nejo,Aaron A Diaz,Husam Babikir,Karin Shamardani,Joanna J Phillips,Susan Chang,Francisca Catalan

doi:10.1186/s13059-021-02259-5

Abstract

BackgroundAlternative splicing is a rich source of tumor-specific neoantigen targets for immunotherapy. This holds promise for glioblastomas (GBMs), the most common primary tumors of the adult brain, which are resistant to standard-of-care therapy. Although most clinical trials enroll patients at recurrence, most preclinical studies have been done with specimens from primary disease. There are limited expression data from GBMs at recurrence and surprisingly little is known about the evolution of splicing patterns under therapy.ResultWe profile 37 primary-recurrent paired human GBM specimens via RNA sequencing. We describe the landscape of alternative splicing in GBM at recurrence and contrast that to primary and non-malignant brain-tissue specimens. By screening single-cell atlases, we identify cell-type-specific splicing patterns and novel splicing events in cell-surface proteins that are suitable targets for engineered T cell therapies. We identify recurrent-specific isoforms of mitogen-activated kinase pathway genes that enhance invasiveness and are preferentially expressed by stem-like cells.ConclusionThese studies shed light on gene expression in recurrent GBM and identify novel targets for therapeutic development.

Highlights

Alternative-splicing (AS) events have recently been identified as a source of neoantigens that are suitable for immunotherapy (e.g., [1])
We identified an exonretention event upregulated in recurrent GBM in mitogen-activated protein 4 kinase 4 (MAP4K4), and we inferred serine- and arginine-rich splicing factor 5 (SRSF5) as an upstream regulator
We found that non-malignant brain samples formed a distinct cluster, separating from primary and recurrent GBM specimens, when viewed in a principal-components analysis (PCA) of marginal percent-selected indices (PSIs) (Fig. 1c; Additional file 2: Table S2)

Summary

Introduction

Alternative-splicing (AS) events have recently been identified as a source of neoantigens that are suitable for immunotherapy (e.g., [1]). This observation has greatly increased the scope of neoantigen targets. Little is known about gene expression in recurrences from primary glioblastomas (GBMs), despite GBM being the most common and most deadly primary adult-brain tumors. Alternative splicing is a rich source of tumor-specific neoantigen targets for immunotherapy. This holds promise for glioblastomas (GBMs), the most common primary tumors of the adult brain, which are resistant to standard-of-care therapy. There are limited expression data from GBMs at recurrence and surprisingly little is known about the evolution of splicing patterns under therapy

Methods

Results

Conclusion