Systematic discovery of neoepitope-HLA pairs for neoantigens shared among patients and tumor types

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Precision cancer immunotherapies rely on validated neoepitopes common across patients and tumor types.
• Current limitations in the repertoire of shared neoantigen-human leukocyte antigen (HLA) complexes hinder broad application.

Purpose of the Study:

• To expand the repertoire of shared neoantigen-HLA complexes.
• To develop a high-throughput platform for identifying and validating novel neoepitope-HLA candidates.

Main Methods:

• Coupled an in vitro peptide-HLA binding assay with engineered cellular models expressing individual HLA alleles.
• Utilized a concatenated transgene harboring 47 common cancer neoantigens.
• Performed biochemical, computational, and immunoprecipitation mass spectrometry analyses.

Main Results:

• Screened over 24,000 neoepitope-HLA combinations.
• Identified 844 unique candidate neoepitope-HLA complexes.
• Validated 86 neoepitope-HLA candidates using mass spectrometry.
• Identified T cell receptors recognizing select neoepitope-HLA pairs, confirming immunogenicity potential.

Conclusions:

• The developed platform successfully identified and validated a significant number of shared neoepitope-HLA complexes.
• These findings provide valuable data and cellular systems for advancing antigen processing research and neoepitope targeting therapies in cancer immunotherapy.