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

Project description

Therapy-induced neo-antigens for precision cancer vaccines

Cancer treatments can create new tumour-specific targets. These therapy-induced neo-antigens can arise from mutations, RNA splicing errors, or post-translational modifications triggered by chemotherapy or targeted therapies. Recognised as foreign by the immune system, they offer a path for personalised immunotherapy, although distinguishing them from normal tumour antigens is challenging. In this context, the ERC-funded TI-uORFe project will develop mRNA vaccines and immunotherapies for triple-negative breast cancer, where drug resistance is common. Using ribosome profiling, researchers will identify non-canonical peptides presented by MHC-I molecules to trigger immune responses. The goal is to boost chemotherapy efficacy and improve patient survival through precision immunotherapy.

Objective

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.

Fields of science (EuroSciVoc)

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

(opens in new window) ERC-2025-POC

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Host institution

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Net EU contribution
€ 150 000,00
Address
IM NEUENHEIMER FELD 280
69120 Heidelberg
Germany
Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
Links
Total cost
No data

Beneficiaries (1)