Modalities to identify clinically actionable neoantigens

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by restoring T cell-mediated antitumor immunity.
• Durable clinical responses to ICIs are limited to a subset of patients, necessitating a deeper understanding of antitumor immunity mechanisms.
• Cancer-specific neoantigens are critical for potent T cell responses and are promising targets for cancer vaccines and adoptive cell therapies.

Purpose of the Study:

• To review current strategies for identifying cancer neoantigens.
• To discuss the challenges and future directions in neoantigen research.
• To highlight the importance of neoantigen immunogenicity validation.

Main Methods:

• Conventional neoantigen identification relies on whole-exome sequencing (WES) of somatic mutations.
• Advanced techniques, including human leukocyte antigen (HLA) ligandome analysis and various sequencing technologies, expand the sources of immunogenic neoantigens beyond somatic mutations.
• Experimental platforms and single-cell RNA/T-cell receptor sequencing are employed to validate neoantigen immunogenicity and identify tumor-reactive T cell clones.

Main Results:

• Whole-exome sequencing (WES) has limitations in identifying a sufficient number of neoantigens.
• Emerging technologies reveal immunogenic peptides from diverse sources, including noncoding regions, as functional neoantigens.
• Direct identification of HLA-presented peptides via HLA ligandome analysis broadens the scope of known neoantigen sources.

Conclusions:

• Neoantigen identification has evolved beyond somatic mutations to include peptides from various genomic regions.
• Experimental validation of neoantigen immunogenicity is crucial but often lacking.
• Future research should focus on refining neoantigen identification and validation strategies to improve cancer immunotherapy efficacy.