Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer...

Area of Science:

• Oncology
• Immunology
• Genomics
• Epigenetics

Background:

• Next-generation sequencing shows varied tumor immunogenicity, but molecular drivers are unclear.
• Endogenous retroviruses (ERVs) can act as tumor-specific neoantigens, but their role in metastatic cancer immunogenicity is not well-established.

Purpose of the Study:

• To investigate the association between ERV levels and immunogenicity across different metastatic cancer types.
• To identify molecular characteristics underlying variations in tumor immunogenicity.

Main Methods:

• Bioinformatics analysis of genomic, transcriptomic, and clinical data from 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma.
• Identification of tumor subgroups based on ERV expression and transcriptional signatures.

Main Results:

• A viral mimicry tumor subgroup was identified in breast, colorectal, and pancreatic cancers, characterized by increased ERV levels and antiviral response signatures.
• Viral mimicry in colorectal and pancreatic tumors correlated with elevated expression of the DNA demethylation gene TET2.
• These findings suggest a link between ERV abundance, epigenetic dysregulation (TET2), and enhanced tumor immunogenicity.

Conclusions:

• An ERV-associated viral mimicry phenotype exists across distinct metastatic cancer types.
• ERV expression, epigenetic dysregulation, and tumor immunogenicity are interconnected.
• This phenotype may represent a targetable mechanism for cancer immunotherapy.