RNA Transcription and Splicing Errors as a Source of Cancer Frameshift Neoantigens for Vaccines

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Checkpoint inhibitors enhance anti-tumor immunity by targeting tumor neoantigens derived from DNA mutations.
• Personalized cancer vaccines are being developed based on identifying tumor-specific neoantigens.
• The origin and immunogenicity of tumor neoantigens are areas of active research.

Purpose of the Study:

• To identify and characterize a novel, previously unrecognized source of tumor neoantigens.
• To investigate the role of microsatellite errors and exon mis-splicing in generating immunogenic neoantigens.
• To develop a method for detecting patient immune responses to these novel neoantigens for potential therapeutic applications.

Main Methods:

• Analysis of microsatellite (MS) transcription errors and exon mis-splicing events in tumor DNA.
• Prediction of frameshift (FS) neoantigen peptide sequences arising from these errors.
• Creation of a peptide array encompassing all potential FS neoantigen peptides.
• Detection of patient antibody responses against FS peptides using the peptide array.

Main Results:

• Microsatellite errors and exon mis-splicing generate highly immunogenic frameshift (FS) neoantigens in tumors.
• The sequences of these FS neoantigens are predictable.
• A peptide array successfully detected personally reactive antibody responses to FS peptides in patients across five cancer types.

Conclusions:

• Microsatellite errors and mis-splicing represent a significant, previously unrecognized source of tumor neoantigens.
• FS neoantigens are predictable and elicit a detectable immune response.
• This discovery provides a new avenue for developing personalized cancer vaccines and immunotherapies.