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Changes in alternative splicing and associated neo-antigens due to therapy

Recent studies have identified alternative splicing (AS) as a novel source of neoantigens for immunotherapy. Surprisingly little is known about the AS milieu in recurrent glioblastoma (GBM), despite this being the venue for most clinical trials. We profiled 29 primary-recurrent paired human GBM specimens via RNA sequencing and re-analyzed RNA-sequencing data from non-malignant human brain tissues. From these data, we reconstructed the landscape of AS in GBM through recurrence and contrasted that to isoforms observed in non-malignant brain. The AS events we identified were cross-referenced with single-cell GBM atlases to determine cell-type specific splicing patterns. From this we identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies. We found recurrent-specific isoforms of mitogen-activated kinase pathway genes which are expressed exclusively by GBM stem-like cells that enhance invasiveness. These studies shed light on the effect of therapy on AS and identify novel targets for emerging immunotherapies.

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Dataset ID Description Technology Samples
EGAD00001006744 Illumina NovaSeq 6000 1
EGAD00001006745 Illumina NovaSeq 6000 1
EGAD00001006747 Illumina NovaSeq 6000 1
EGAD00001006748 Illumina NovaSeq 6000 1
EGAD00001006749 Illumina NovaSeq 6000 1
EGAD00001006750 Illumina NovaSeq 6000 1
EGAD00001006751 Illumina NovaSeq 6000 1
EGAD00001006752 Illumina NovaSeq 6000 1
EGAD00001006753 Illumina NovaSeq 6000 1
EGAD00001006754 Illumina NovaSeq 6000 1
EGAD00001006755 Illumina NovaSeq 6000 1
EGAD00001006756 Illumina NovaSeq 6000 1
EGAD00001006757 Illumina NovaSeq 6000 1
EGAD00001006758 Illumina NovaSeq 6000 1
EGAD00001006759 Illumina NovaSeq 6000 1
EGAD00001006760 Illumina NovaSeq 6000 1
EGAD00001006761 Illumina NovaSeq 6000 1
EGAD00001006762 Illumina NovaSeq 6000 1
EGAD00001006763 Illumina NovaSeq 6000 1
EGAD00001006764 Illumina NovaSeq 6000 1
EGAD00001006765 Illumina NovaSeq 6000 1
EGAD00001006766 Illumina NovaSeq 6000 1
EGAD00001006767 Illumina NovaSeq 6000 1
EGAD00001006768 Illumina NovaSeq 6000 1
EGAD00001006769 Illumina NovaSeq 6000 1
EGAD00001006770 Illumina NovaSeq 6000 1
EGAD00001006771 Illumina NovaSeq 6000 1
EGAD00001006772 Illumina NovaSeq 6000 1
EGAD00001006773 Illumina NovaSeq 6000 1
EGAD00001006830 Illumina NovaSeq 6000 1
EGAD00001006831 Illumina NovaSeq 6000 1
EGAD00001006832 Illumina NovaSeq 6000 1
EGAD00001006833 Illumina NovaSeq 6000 1
EGAD00001006834 Illumina NovaSeq 6000 1
EGAD00001006835 Illumina NovaSeq 6000 1
EGAD00001006836 Illumina NovaSeq 6000 1
EGAD00001006837 Illumina NovaSeq 6000 1
Publications Citations
The evolution of alternative splicing in glioblastoma under therapy.
Genome Biol 22: 2021 48
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