Beneath the Surface: Neoantigens beyond Chromosomal DNA Mutations

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Conventional understanding attributes neoantigen generation primarily to chromosomal DNA mutations.
• Emerging evidence indicates that posttranscriptional and posttranslational modifications also yield significant neoantigens.
• Understanding diverse neoantigen sources is critical for advancing cancer immunotherapy.

Purpose of the Study:

• To review known and potential nonchromosomal sources of neoantigens.
• To discuss emerging technologies for neoantigen identification and characterization.
• To explore clinical trials investigating nonchromosomal neoantigens for next-generation cancer immunotherapies.

Main Methods:

• Literature review and synthesis of current research on neoantigen generation.
• Analysis of emerging technologies in neoantigen discovery (e.g., transcriptomics, proteomics).
• Overview of ongoing and completed clinical trials related to nonchromosomal neoantigens.

Main Results:

• Nonchromosomal events, including RNA editing and protein modifications, are confirmed sources of neoantigens.
• Advanced sequencing and proteomic techniques are enhancing the identification of these diverse neoantigens.
• Clinical trials are beginning to explore immunotherapies based on non-DNA mutation-derived neoantigens.

Conclusions:

• Nonchromosomal neoantigens represent a significant, often overlooked, source of tumor-specific antigens.
• Harnessing these neoantigens could redefine tumor immunogenicity classification ('hot/cold' tumors).
• This expanded understanding paves the way for more effective and personalized immunotherapeutic strategies.