Cancers modulate p53 truncal neoantigen display to evade T cell detection

Area of Science:

• Oncology
• Immunology
• Proteomics

Background:

• TP53 mutations are early cancer events, often encoding tumor-specific neoantigens.
• These neoantigens are presumed targets for cytotoxic T lymphocytes (CTLs).
• Systematic analysis of p53 peptide-MHC (pMHC) cell surface display, antigenicity, and immunogenicity is lacking.

Purpose of the Study:

• To develop and apply an epitope discovery platform for identifying p53-derived pMHCs on cancer cells.
• To investigate the presentation, antigenicity, and immunogenicity of p53 neoantigens.
• To understand mechanisms limiting effective neoepitope targeting in established tumors.

Main Methods:

• Developed an epitope discovery platform using p53-reconstituted lung cancer cells and tumor cells as pMHC sources.
• Employed data-independent acquisition mass spectrometry (MS) for attomole sensitivity pMHC identification.
• Combined MS with nanoscale chromatography and advanced peptide detection techniques.

Main Results:

• Identified a limited set of p53 pMHCs presented by common human leukocyte antigen (HLA) alleles, excluding ~97% of predicted neoepitopes.
• Observed that surface neoantigens are restricted and unaffected by enhanced p53 turnover.
• Discovered immune selection against MHC alleles and ERAP1-mediated destruction limit high-affinity neoepitopes in tumors.
• Found that the R175H/HLA-A*02:01 neoepitope escapes immune selection due to weak MHC affinity.

Conclusions:

• Only a small fraction of potential p53 neoantigens are physically presented on cancer cell surfaces.
• Tumor immunoediting mechanisms, including MHC allele selection and ERAP1 activity, restrict the repertoire of targetable neoepitopes.
• Effective targeting of truncal neoepitopes requires precise MS analysis and functional validation for successful cancer immunotherapy.