Five dominant amino acid substitution signatures shape tumour immunity

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Numerous mutational processes occur in cancer, but their functional impacts, particularly on immune recognition, remain unclear.
• The hypothesis is that specific mutation sources generate amino acid substitutions (AAS) that evade immune detection, leading to immune-cold tumors irrespective of tissue type or mutation burden.

Purpose of the Study:

• To investigate the functional impacts of various mutational processes in cancer.
• To map the links between mutagens, DNA-repair defects, and distinct amino acid substitution signatures (AAS).
• To understand how neoantigen quality influences anti-tumor immunity and immunotherapy response.

Main Methods:

• Analysis of 9300 cancer exomes.
• In silico prediction and experimental mutagenesis studies.
• Correlation analysis between specific AAS, tumor microenvironments, and human leukocyte antigen (HLA) class I variants.

Main Results:

• The mutational spectrum collapsed into five recurrent AAS with distinct functional profiles.
• AAS4, associated with alkylating agents and mismatch-repair (MMR) deficiency, yields poorly immunogenic neopeptides, resulting in immune-desert tumors with poor immunotherapy response.
• Certain HLA class I variants, like HLA-B*07:02, correlate with immune-hot tumors in the AAS4 subgroup by presenting proline-enriched neopeptides, stimulating T-cell proliferation.

Conclusions:

• Neoantigen quality, not solely quantity, is critical for anti-tumor immunity.
• The findings explain variable immunotherapy responses in MMR-deficient cancers.
• Amino acid substitution patterns should be incorporated into predictive biomarkers and cancer therapy design.