Project summary:

In the last decades cancer immunotherapy has gained remarkable attention with improved patient’s outcome. However, some tumors develop resistance and the treatment becomes inefficient. Usually, tumor resistance is caused by down regulation of the antigens presentation to the cell surface, which allows tumor cells to become “invisible” and escape from cytotoxic T cells attack. By restoring antigens presentation pathway, the tumor cells become visible to the immune system and allow efficient T cells recognition and tumor clearance. Antigens presenting machinery relies on key processes such as: antigenic peptides production, processing and (Major Histocompatibility Complex) MHC class I loading. In this project we will develop a model of melanoma cells able to display an increased amount of antigenic peptides to the cell surface and will also perform screening experiments for identification of new melanoma epitopes. Using a melanoma model cell line we aim to target for the first time three key processes of the antigen presentation pathway by the following strategies: 1) selection of the antigens for degradation by CRISPR activation of Endoplasmic Reticulum Associated Degradation (ERAD) components, 2) modulating proteases activity for enhancing cytosolic production of the antigens and 3) activation of MHC class I presentation promoter in parallel with diverting antigen presentation to the endocytic-recycling pathway. These strategies should result in increased antigens presentation diversity at the melanoma cells surface and identification of new melanoma antigens. Discovery of new antigens may have crucial clinical relevance since it was shown that efficacy of PD1/PDL-1 therapy is improved when immunity was previously boosted and that combination of immunotherapy with chemo/radiotherapy gives best clinical outcome.