A Cancer Prevention Dendritic Cell Vaccine: Frameshift-Derived Neoantigens as Immunopreventive Targets in Lynch Syndrome
[eng] Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with pathogenic germline variants in DNA mismatch repair (MMR) genes. The deficiency in this repair system leads to an accumulation of mutations, particularly in repetitive sequences, resulting in mi...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223995 |
| Acesso em linha: | https://hdl.handle.net/2445/223995 http://hdl.handle.net/10803/695638 |
| Access Level: | acceso abierto |
| Palavra-chave: | Càncer colorectal Immunoteràpia Vacunes Antígens tumorals Cèl·lules dendrítiques Colorectal cancer Immunotheraphy Vaccines Tumor antigens Dendritic cells |
| Resumo: | [eng] Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with pathogenic germline variants in DNA mismatch repair (MMR) genes. The deficiency in this repair system leads to an accumulation of mutations, particularly in repetitive sequences, resulting in microsatellite instability (MSI) and the presence of specific neoantigens derived from frameshift mutations. Despite advances in surveillance and prevention strategies, LS carriers continue to face a high lifetime risk of developing multiple tumours. This thesis investigates the potential of neoantigens generated by frameshift mutations in mononucleotide repeat (MNR) sequences as immunotherapeutic targets for cancer prevention in LS carriers. Genomic data from frequent mutations in MSI tumours and precancerous lesions were analysed with the goal of identifying variants shared among patients and of prioritizing those with the highest immunogenic potential. Using bioinformatics tools, frameshift sequences were selected based on their high likelihood of being presented by various Human Leukocyte Antigen (HLA) alleles, and thus recognized by the immune system of the majority of the population. Once these sequences were selected, the presence of their associated mutations was validated in different tumour types, revealing that a significant proportion of these neoantigens are shared among various MSI cancers, both LS-related and unrelated. This suggests the existence of a common neoantigen profile in MMR-deficient tumours, potentially allowing for broader application of our vaccine. In vitro experiments confirmed the immunogenicity of the selected neoantigens, showing they can be recognized by T lymphocytes from LS patients, regardless of cancer history. This supports the hypothesis that these individuals develop immune responses and eliminate MSI lesions even before clinical detection, generating immunological memory that could be enhanced through vaccination. On this basis, a preventive dendritic cell (DC)-based vaccine was developed, composed of a selection of the most promising neoantigens. Using these cells at a preventive stage retains their full potential to induce robust and physiological immune responses. This formulation will be evaluated in a phase Ib clinical trial, whose main goal is to determine the vaccine’s safety and its ability to induce a protective immune response in LS carriers. Preliminary results from the validation phases of the trial show that the strategy is feasible and that there is specific recognition of certain neoantigens by T cells in individuals prior to vaccination, suggesting relevant preventive potential. Overall, this thesis demonstrates that neoantigens derived from frameshift mutations represent a promising strategy for the development of immunotherapies and immunoprevention approaches in LS and other MSI tumours, marking a step forward in improving the quality of life for these individuals. |
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