Noncoding regions are the main source of targetable tumor-specific antigens

Area of Science:

• Oncology
• Immunology
• Genomics
• Proteomics

Background:

• Tumor-specific antigens (TSAs) are crucial for effective cancer immunotherapy.
• The identification of novel TSAs has been limited, hindering therapeutic development.
• Existing methods primarily focus on coding regions, potentially missing many TSA candidates.

Purpose of the Study:

• To develop and validate a high-throughput proteogenomic approach for discovering TSAs from all genomic regions.
• To identify novel TSAs in murine cancer cell lines and human primary tumors.
• To establish criteria for prioritizing identified TSAs for clinical application.

Main Methods:

• A proteogenomic strategy was employed for high-throughput TSA discovery.
• Analysis was performed on two murine cancer cell lines and seven human primary tumors.
• Antitumor immune responses in mice were assessed following TSA vaccination.

Main Results:

• A total of 40 TSAs were identified across the tested samples.
• Approximately 90% of the identified TSAs originated from noncoding genomic regions.
• Most TSAs were derived from aberrantly expressed, nonmutated transcripts, including endogenous retroelements.
• TSA expression levels and pre-existing T-cell frequencies influenced antitumor responses in mice.

Conclusions:

• The developed proteogenomic approach significantly expands the discovery of potential cancer immunotherapy targets.
• Novel TSAs, particularly those from noncoding regions and shared across tumor types, offer promising avenues for treatment.
• TSA expression and T-cell repertoire analysis can guide the prioritization of TSAs for clinical translation.