TI-uORFe · Exploiting Therapy-Induced Neo-Epitopes to Overcome Drug Resistance in Triple-Negative Breast Cancer

Therapy-induced neo-antigens represent a novel class of tumor-specific antigens that arise from therapeutic interventions such as chemotherapy and targeted therapies. These neo-antigens, resulting from genomic mutations, aberrant post-translational modifications, and dysregulated RNA splicing, are recognized by the immune system as foreign, prompting an immune response that bypasses central tolerance mechanisms. Despite advancements in next-generation sequencing and bioinformatics that facilitate the identification of these neo-antigens, distinguishing drug-induced neo-antigens from inherent tumor antigens remains a significant challenge. This proof-of-concept proposal aims to leverage therapy-induced neo-antigens to develop personalized cancer vaccines and immunotherapies, particularly targeting triple-negative breast cancer (TNBC), where drug resistance is prevalent.By utilizing ribosome profiling, we have identified non-canonical peptides translated from therapy-induced changes in cancer cells, which are presented by MHC-I molecules and recognized by T lymphocytes, leading to specific tumor cell killing. Our approach focuses on generating mRNA vaccines based on these neo-epitopes, with the goal of enhancing chemotherapy responses and overcoming drug resistance. The proposed research will address critical bottlenecks in neo-epitope therapy, including accurate identification of immunogenic neo-epitopes and validation of immunogenicity in preclinical models. Ultimately, this innovative strategy aims to improve therapeutic efficacy and patient outcomes in TNBC, offering a transformative approach to combat drug resistance and enhance survival rates.