Identifying Strong Neoantigen MHC-I/II Binding Candidates for Targeted Immunotherapy with SINE.

Area of Science:

• Oncology
• Immunology
• Bioinformatics

Background:

• Tumor-derived neoantigens elicit immune responses via MHC-I/II binding, advancing immunotherapy.
• Identifying neoantigens from non-synonymous mutations is limited in some cancers, necessitating alternative approaches like aberrant splicing.

Purpose of the Study:

• To develop a computational pipeline, the splice isoform neoantigen evaluator (SINE), for identifying neoantigens arising from aberrant splicing.
• To assess the immunogenic potential of peptides derived from alternative splicing events.

Main Methods:

• Developed the SINE pipeline to detect peptides from spliced/inserted genomic regions.
• Calculated MHC-I/II binding affinity for these peptides across the human leukocyte antigen landscape.
• Utilized Patient Harmonic-mean Best Rank scores for peptide evaluation.

Main Results:

• Identified 125 potentially immunogenic splicing events and 9 principal binders in head and neck cancer patients.
• Found that wild-type peptides corresponding to these binders had no MHC-I/II affinity.
• In a melanoma cohort, SINE-identified splicing events predicted response to anti-PD1 therapy.

Conclusions:

• SINE effectively identifies clinically relevant immunogenic neojunctions from aberrant splicing.
• This tool expands the understanding of the neoantigen landscape beyond mutations.
• SINE offers a valuable resource for cancer immunotherapy research.