Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Microsatellite instability-high (MSI-H) tumors exhibit high mutation rates and respond well to immunotherapy.
• Frameshift mutations are common in MSI-H cancers, leading to the production of novel tumor antigens.

Purpose of the Study:

• To identify shared frameshift mutations and their encoded epitopes in MSI-H cancers.
• To assess the immunogenicity and potential of these neoantigens for cancer vaccine development.

Main Methods:

• Analysis of indel mutations in MSI-H endometrial, colorectal, and stomach cancers.
• Prediction of epitope binding to common MHC alleles.
• T-cell stimulation experiments using peripheral blood mononuclear cells.

Main Results:

• Identified shared frameshift mutations encoding multiple epitopes across different MSI-H cancer types.
• These epitopes demonstrated high population occurrence, broad tumor subclone presence, and predicted binding to frequent MHC alleles.
• Frameshift-derived neoantigens are distinct from self/viral antigens and showed confirmed immunogenicity in vitro.

Conclusions:

• Tumor-specific antigens derived from shared frameshift mutations are widespread and highly immunogenic in MSI-H and Lynch syndrome patients.
• These findings present a promising avenue for designing common, off-the-shelf cancer vaccines.