Dottorato in SCIENZE DELLA VITA

Titolo della tesi: ERAP1 modulation as an innovative strategy for cancer treatment

The recent development of immune checkpoint blockade (ICB)-mediated immunotherapy has achieved outstanding clinical results in patients with a broad spectrum of cancer types, improving their overall survival. Despite the encouraging results, the number of patients who can benefit and have a long-term response to treatment is limited. Recent evidence shows that defects in the antigen processing and presentation (APP) machinery in tumor cells can positively influence the response to ICB-based therapy and the levels of tumor-infiltrating lymphocytes. A key enzyme in the APP machinery is the endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1), which plays a crucial role in generating peptides of the optimal length to bind major histocompatibility complex class I (MHC-I) molecules. Inhibition of ERAP1 has been associated with an increase in antitumor immunity mediated by Natural Killer (NK) and cytotoxic T-cells in murine and human tumors, suggesting that it could represent an attractive target for enhancing the antitumor response. Therefore, dissecting the role of ERAP1 in tumor progression is crucial and may lead to the discovery of new synergies in cancer immunotherapy. Here we investigated the extent to which ERAAP shapes the tumor microenvironment (TME) of ‘hot’ and ‘cold’ murine melanoma models. We found that inhibition of ERAAP (the murine orthologue of ERAP1) induces important changes in the immunopeptidome of melanoma cells, making them more susceptible to immune cell-mediated killing by increasing the activation state of T-cells and NK-cells. In ‘hot’ melanoma tumors, ERAAP inhibition restrains their growth in vitro and in vivo by recruiting activated NK-cells to tumors. Interestingly, in ‘cold’ melanoma models, the absence of ERAAP is not sufficient to control tumor growth but is able to reshape the immune infiltrate in the TME. These results highlight the need to identify biomarkers of response to ERAAP inhibition and to find new synergies to improve clinical outcomes of patients with melanoma and other tumors.