Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates

Abstract

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.