Het benutten van het pyrimidinemetabolisme om immunosuppressie bij alvleesklierkanker te overwinnen

Immunotherapy has revolutionized the way we treat cancer. Unfortunately, many patients remain unresponsive, partly due to the harsh conditions within the tumor micro-environment (TME).<br />Metabolic fluctuations, as well as a derailed nucleotide metabolism, can be employed by the TME to orchestrate a potent immunosuppressive interplay between cancer cells and tumorinfiltrating immune cells. Interestingly, our preliminary data show that cytidine deaminase (CDA) is among the most upregulated metabolic genes in several immunotherapy-resistant mouse and patient tumors. Induction of CDA in cancer cells promotes uridine-diphosphate (UDP) production and release. We hypothesize that cancer cell derived-UDP can be sensed by tumor-associated macrophages (TAMs) upon UDP binding to their cognate P2Y receptors. The activation of this pyrimidinergic signalling results in the infiltration and preservation of the immunosuppressive phenotype in TAMs that, consequently, abate CD8+ T cell recruitment to the tumor and their cytotoxic functions. Unravelling this unexplored crosstalk between cancer cells and TAMs will lead us to achieve our ultimate goal of disrupting TAMmediated immunosuppression and promoting cytotoxic T cell (CTL) infiltration and activation. Since the absence of tumor-infiltrating CTLs can explain at large the disappointing clinical results of current immunotherapeutics, we envision our new approach to enable the efficacy of α-PD-1 therapy.