STIMUNO · Searching for novel strategies improving cancer immunotherapy

The main goal of this project is to explore new fundamental pathways involved in the regulation of antitumor immune response. Since the immunosuppressive tumor microenvironment constitutes a key barrier to effective immunotherapy, our predominant ambition is to characterize novel, hitherto unknown metabolic changes that can support the survival of tumor cells and the escape from the immune surveillance. We have recently discovered a new metabolite within tumor microenvironment with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. Within the project, we plan to corroborate on our preliminary findings in order to establish the role of this factor in mitigating antitumor immune response. To this end, we will determine the level of its production within tumors in murine models. Moreover, we will relate these findings to human data by analysing the immune milieu and the expression of enzymes involved in generation of this metabolic agent in a cohort of cancer patients. We will also investigate the mechanisms by which this factor could perturb the functions of tumor-infiltrating effector cells.Finally, we aspire to use the knowledge gained during the implementation of this project to propose innovative therapeutic solutions. Specifically, we will investigate whether and how the inhibition of selected enzymes involved in the generation of this new metabolic checkpoint can impact on the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors, arginase inhibitors as well as adoptive therapy with CAR-T cells and CAR-NK cells. We strongly believe that by achieving the goals of our project we will make a significant step forward in order to develop and to design cutting-edge therapeutic strategies. These compelling solutions would further improve the efficacy of tumor immunotherapy, thus contributing to a breakthrough advance in cancer treatment.