Proteogenomic analysis identifies neoantigens and bacterial peptides as immunotherapy targets in colorectal cancer

Area of Science:

• Oncology
• Immunology
• Genomics
• Proteomics

Background:

• Cancer immunotherapy has advanced significantly, yet response rates in colorectal cancer (CRC) remain limited due to a lack of effective targets.
• Identifying specific targets is crucial for developing more effective immunotherapies for CRC patients.

Purpose of the Study:

• To identify novel neoantigens and bacterial peptides as potential antitumor targets in colorectal cancer (CRC) using a proteogenomic approach.
• To evaluate the immunogenicity of identified targets and their potential for T cell activation in CRC.

Main Methods:

• Employed a proteogenomic strategy combining immunopeptidomics, whole exome sequencing, and 16S ribosomal DNA sequencing on samples from 8 CRC patients.
• Utilized immunoassays to assess T cell recognition of identified neoantigens and bacterial immunopeptides.
• Performed T cell receptor (TCR) αβ sequencing and functional studies to analyze T cell responses.

Main Results:

• Successfully identified personalized neoantigens and bacterial immunopeptides in CRC patients.
• Demonstrated that all identified neoantigens and 5 of 8 bacterial immunopeptides were recognized by autologous T cells.
• Confirmed T cell receptor-T (TCR-T) activation by epitope-pulsed cells, highlighting the immunogenicity of the targets.

Conclusions:

• This comprehensive profiling of the colorectal cancer (CRC) immunopeptidome has revealed several promising neoantigens and bacterial peptides.
• These identified targets hold significant potential for the development of novel, personalized immunotherapy strategies for CRC.
• The findings support the use of proteogenomic approaches for discovering actionable targets in cancer immunotherapy.