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SpliceMutr Enables Pan-Cancer Analysis of Splicing-Derived Neoantigen Burden in Tumors.
Theron Palmer1,2, Michael D Kessler2,3, Xiaoshan M Shao1
1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
Cancer Research Communications
|October 29, 2024
Summary
Aberrant alternative splicing creates neoantigens that trigger immune responses. A new tool, SpliceMutr, identifies these splicing-derived neoantigens and reveals their link to antitumor immunity and immunotherapy response.
Area of Science:
- Immunology
- Bioinformatics
- Genomics
Background:
- Aberrant alternative splicing can generate neoantigens, potentially stimulating immune responses.
- Existing methods for quantifying splicing-derived neoantigens have limitations, including reliance on independent references and susceptibility to batch effects.
Purpose of the Study:
- To introduce SpliceMutr, a bioinformatics pipeline for identifying splicing-derived neoantigens from tumor and normal data.
- To analyze splicing antigenicity across The Cancer Genome Atlas (TCGA) and investigate its relationship with antitumor immunity and immunotherapy response.
Main Methods:
- Developed SpliceMutr, a computational pipeline for identifying tumor-specific antigenic splice variants.
- Predicted MHC-binding affinity and estimated splicing antigenicity scores per gene.
- Applied SpliceMutr to TCGA transcriptomic data and analyzed cohorts of melanoma patients treated with immune checkpoint inhibitors.
Main Results:
- Identified splicing-derived neoantigens and antigenicity scores across cancer types, finding correlations with antitumor immunity biomarkers.
- Observed higher splicing antigenicity in tumors compared to normal tissues and in patients with mutations in splicing machinery genes.
- Found that splicing antigenicity changes in response to immune checkpoint inhibitor (ICI) therapies, with increased antigenicity in responders and decreased antigenicity in non-responders (progressors).
Conclusions:
- SpliceMutr provides a novel computational approach for analyzing splicing antigenicity.
- Splicing antigenicity is higher in tumors, influenced by splicing machinery mutations, and associated with immunotherapy response.
- Further pan-cancer studies are needed to elucidate the interplay between splicing antigenicity and ICI response.
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