Primary or acquired resistance to immune checkpoint blockade (ICB) is the main challenge in treatment of metastasized melanoma. Recent work emphasizes the importance of MHC class I and class II antigen presentation for response to ICB, as loss of MHC expression has been found in melanoma samples from patients who acquired resistance to ICB. The Polycomb Repressive Complex 2 (PRC2) has been identified to maintain bivalency at the promotors of MHC-I antigen-processing pathway genes to repress their expression.
This project is based on the hypothesis that the inhibition of EZH2, an enzymatic component of PRC2, can restore MHC class I and II antigen presentation on melanoma cells and enable responses to ICB. Inhibition of PRC2 might be an effective new therapeutic strategy to overcome primary resistance to ICB through restoration of MHC class I and II antigen presentation in melanoma patients. The goal of this project is to gain a deeper mechanistic understanding of how PRC2 influences response to ICB in melanoma and to transfer the experience and knowledge gained to cutaneous lymphoma.