Low immunogenicity of common cancer hot spot mutations resulting in false immunogenic selection signals

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Cancer arises from somatic mutations conferring cellular fitness advantages.
• The immune system counters cancer via neoantigens presented by Human Leukocyte Antigen (HLA) molecules.
• HLA genotype may influence cancer mutation patterns by affecting neoantigen presentation.

Purpose of the Study:

• To investigate whether Human Leukocyte Antigen (HLA) affinity differences for cancer mutations are linked to Major Histocompatibility Complex (MHC) genotype variation.
• To identify mechanisms driving observed differences in HLA affinity for cancer-associated mutations.

Main Methods:

• Generation of virtual patients with a uniform MHC genotype.
• Analysis of HLA affinity for observed and unobserved mutations across 13 hot spot driver mutations in 6 genes.
• Identification of oncogenic mechanisms affecting peptide-HLA affinity.

Main Results:

• HLA affinity differences for mutations are independent of MHC genotype variation.
• High frequencies of specific driver mutations (e.g., in BRAF, TP53, KRAS) correlate with reduced peptide-HLA affinity.
• Mechanisms include phospho-mimicking substitutions, destabilizing mutations, and specific mutational contexts.

Conclusions:

• Observed HLA affinity variations in cancer are primarily driven by mutation characteristics, not MHC genotype.
• Certain oncogenic mutations inherently reduce neoantigen presentation potential.
• HLA affinity predictions require careful interpretation in the context of immunogenic selection.