Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates
Menée à l'aide de modèles murins de mélanome humain ou de cancer du sein triple négatif, cette étude met en évidence l'intérêt d'un vaccin antitumoral se composant de nanoparticules lipidiques ciblant les ganglions lymphatiques et libérant des antigènes tumoraux conjugués à des ligands qui peuvent se lier à des ubiquitine ligases E3
The activation of cytotoxic T cells against tumour cells typically requires the cross-presentation, by antigen-presenting cells (and via major histocompatibility complex class I molecules), of an epitope derived from a tumour antigen. A critical step in antigen processing is the proteolysis of tumour antigens mediated by the ubiquitin–proteasome pathway. Here we describe a tumour vaccine leveraging targeted antigen degradation to augment antigen processing and cross-presentation. Analogous to proteolysis-targeting chimaeras, the vaccine consists of lymph-node-targeting lipid nanoparticles encapsulated with tumour antigens pre-conjugated with ligands that can bind to E3 ubiquitin ligases. In mice with subcutaneous human melanoma or triple-negative breast cancer, or with orthotopic mouse Lewis lung carcinoma or clinically inoperable mouse ovarian cancer, subcutaneously delivered vaccines prepared using tumour lysate proteins elicited antigen-specific adaptive immunity and immunological memory, and inhibited tumour growth, metastasis and recurrence, particularly when combined with immune checkpoint inhibition.
Nature Biomedical Engineering , article en libre accès, 2024