Research Project
Impact of PROTAC-mediated HPV16 E6/E7 degradation on viral antigen presentation and T cell-driven tumor cell killing
The HPV oncoproteins E6 and E7, essential for uncontrolled cell proliferation, are ideal therapy targets but their inhibition has a limited effect due to the need to efficiently target every cancer cell. Proteolysis Targeting Chimeras (PROTACs) are small molecules triggering proteasomal degradation of target proteins, and additionally are enhancing MHC-presentation of target protein-derived peptides on the cell surface. This project aims to investigate whether PROTAC-mediated HPV E6/E7 degradation potentiates the efficacy of HPV therapeutic vaccination, by increasing viral antigen presentation on target cells. We will characterize HPV16 E6/E7-derived peptides presented on MHC-I after PROTAC-mediated degradation by mass spectrometry-based immunopeptidomics and assess the potential increase in tumor immunogenicity by cytotoxicity assays. Then, we will assess the combination of HPV16 E6/E7 PROTAC-mediated degradation and therapeutic vaccination in orthotopic tumor models in MHC-humanized A2.DR1 mice.