Identification of immunodominant ERV peptides critical for anti-metastatic immunity in a model of TNBC

Abstract

The integration of immunotherapy into neoadjuvant treatment for triple-negative breast cancer (TNBC) has improved outcomes in some patients. Pre-clinical investigation of immunotherapy resistance in the aggressive 4T1 TNBC model has been hampered by a lack of known tumour-specific epitopes. Using proteomic and functional analyses, we show that metastatic 4T1 subclones downregulate antigen processing and presentation to evade adaptive immunity, a defect reversible by type I interferon (IFN) signaling. Immunopeptidomic profiling revealed that immune responses against metastatic 4T1 subclones largely target cryptic peptides derived from endogenous retroviral (ERV) products, particularly murine leukaemia virus (MLV). IFN treatment enhanced both the abundance and diversity of MLV-derived peptides in the 4T1 immunopeptidome. Moreover, MLV-specific T cell responses were critical for effective immune checkpoint blockade, suppression of tumour growth and prolonged metastasis-free survival. The identification of endogenous, immunodominant ERV epitopes in the widely used 4T1 TNBC model establishes a new platform for ERV-targeted immunotherapy development and provides a foundation for translating IFN and ERV-targeting strategies into future clinical trial design.