Description du projet
Disséquer la réponse aux inhibiteurs de point de contrôle immunitaire
Notre système immunitaire contient naturellement des protéines de point de contrôle qui empêchent les réponses immunitaires fortes de tuer les cellules normales. Les inhibiteurs de point de contrôle immunitaire ont émergé comme une approche d’immunothérapie qui renverse ce blocage et permet aux lymphocytes T de tuer les cellules cancéreuses. Toutefois, l’efficacité clinique des inhibiteurs de point de contrôle immunitaire est limitée, sans expansion flagrante des lymphocytes T au sein des tumeurs. Financé par le Conseil européen de la recherche, le projet EXPAND IT recourra à une approche pluridisciplinaire pour examiner plus en détail et au niveau unicellulaire le mode d’action de ces inhibiteurs. L’accent sera mis sur les lymphocytes T qui se développent, leur localisation au sein du microenvironnement de la tumeur, et les antigènes associés au cancer contre lesquels ils sont dirigés.
Objectif
Cancer immunotherapy using immune checkpoint blockade (ICB) has revolutionized the treatment of advanced-stage cancers. One of the major limitations of ICB is that durable responses are observed only in a subset of patients and in some specific cancer types. We recently analyzed tumor biopsies from breast cancer patients collected during ICB and indeed observed only in a subset of patients that tumor-infiltrating T-cells undergo rapid expansion when exposed to ICB. We characterized the gene expression programs underlying this expansion at single-cell level and realized that - although these expanding T-cells are the main executors of therapeutic response to ICB - several key questions regarding their function remain unanswered. First, we lack accurate knowledge about where in the heterogeneous tumor microenvironment (TME) and in which metabolic niches T-cell expansion occurs. Secondly, based on their TCR sequence we cannot predict upfront which T-cells will expand (or rather act as bystander T-cells), nor can we say to which tumor antigens these expanding T-cells are directed. Thirdly, it is not known which molecular events underlie the generation of the tumor antigens regulating T-cell expansion. Fourthly, we also observed an expansion of the B-cell repertoire and were left with similar questions as for expanding T-cells. For instance, where are expanding B-cells located, how do they interact with expanding T-cells, and do they perhaps even recognize the same tumor antigens. In EXPAND IT, we will use several innovative (single-cell) technologies to provide answers to these questions. These insights will much better characterize the mechanisms driving response to ICB, but will also provide important answers on how to sensitize patients not responding to ICB. Our findings could also contribute to the discovery of high-avidity anti-tumor TCRs that can be used in novel TCR-based cellular therapies.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
9052 ZWIJNAARDE - GENT
Belgique