Description du projet
Bloquer la réparation de l’ADN déclenche l’immunité anticancéreuse
La réparation des mésappariements (MMR pour «mismatch repair») de bases d’ADN est une voie biologique conservée qui joue un rôle clé dans le maintien de l’intégrité génomique en détectant et en corrigeant des erreurs qui surgissent lors de la réplication de l’ADN. Étonnamment, les cancers présentant une déficience dans la MMR répondent correctement à l’immunothérapie et permettent d’obtenir des résultats globalement favorables. Le projet TARGET, financé par l’UE, estime que cette observation se fonde sur le fait que ces types de cancer accumulent les mutations, en sécrétant des néoantigènes qui déclenchent l’immunosurveillance. Le consortium testera si le blocage de la MMR par des médicaments peut provoquer une réponse immunitaire anticancéreuse et stopper la croissance tumorale. Les résultats fourniront des connaissances fondamentales sur l’immunité anticancéreuse et jetteront les bases pour le développement d’une nouvelle classe de médicaments anticancéreux.
Objectif
This project will test for the first time the hypothesis that therapeutic inactivation of DNA repair pathways in cancer cells can be exploited for patient benefit by reawakening an anti-tumor immune response.
Genomic instability and molecular heterogeneity, which occur in cancer cells with DNA repair deficiencies, fuel tumour progression and are associated with poor outcome. An exception is represented by Mismatch repair (MMR) deficient cancers as these tumours are exceedingly genetically heterogeneous but show favourable prognosis and remarkable response to immunotherapy.
The molecular basis for the clinical outcome of MMR deficient cancers has long remained a mystery. Only recently it has become apparent that their biological properties are associated with increased levels of mutations, which unleash adaptive immunity and trigger immunosurveillance.
We have reported that when MMR is impaired, cancers cells grow in immune-deficient mice but are unable to do so in immune competent animals. MMR inactivation increased the mutational burden and led to dynamic mutational profiles, resulting in persistent renewal of neoantigens and engagements of antigen-specific T cells.
These data suggest an unprecedented high risk-high gain approach: the pharmacological blockade of proteins involved in DNA-repair as an anticancer therapy. This unconventional strategy builds on the concept that the immune system can identify and selectively target tumor cells carrying DNA alterations.
Using in vitro and in vivo functional assays we will systematically assess whether and how inactivation of DNA repair genes provokes an immune response and restrict cancer growth. Notably, TARGET will discover and develop inhibitors of MMR and other DNA repair proteins that induce tumor immunity.
The identification of DNA repair pathways which, when disabled, reawaken the immune system will provide transformative knowledge and could lead to the development of an entirely new class of anticancer drugs.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
10124 Torino
Italie