Combination of IDO1-PI3Kgamma/delta axis inhibition and tumor associated antigens DNA vaccination to cure pancreatic cancer; finanziato dall’Unione europea – Next Generation EU

Pancreatic ductal adenocarcinoma (PDA) is still an urgent medical need with little advances in therapy and patient survival. New poly chemotherapy regimens recently employed have been shown to improve outcomes in metastatic patients and also represent an attractive neoadjuvant treatment strategy for locally advanced disease. Targeting the immune system is an active area of research and includes different approaches to improve host immune system fitness. Our preliminary data have demonstrated that vaccination with the tumor associated antigen (TAA) alpha-enolase (ENO1), in association with a PhosphoInositide-3-Kinase (PI3K) dual inhibitor, reduces tumor burden in genetically engineered mice that spontaneously develop PDA. We have also shown that in PDA mouse models genetic inhibition of PI3Kgamma(g) and pharmacological inhibition of PI3Kg/delta(d) strengthen the anticancer immune response, especially in combination with ENO1 vaccination and that humoral and cytotoxic specific anti-ENO1 antibody response plays a critical role in influencing the effect of therapy and significantly reduces tumor lesion. We have also demonstrated that PI3Kd is recruited to indoleamine 2,3-dioxygenase 1 (IDO1) and has a role in mediating IDO1 signal transduction. In addition, our preliminary data suggest that also PI3Kg is involved in IDO1-mediated signaling events, although it cannot be directly bound to IDO1. Selective inhibitors of PI3Kg and PI3Kd significantly impaired TGFbeta (b)-mediated induction of Ido1 in plasmacytoid dendritic cells (pDCs), while IFNgamma (g) failed to induce IDO1 expression in PDA cell lines derived from PI3Kg deficient mice. These data suggest the existence of a functional relationship between IDO1 and PI3Kg/d in controlling immune response suppression. Therefore, co-administration of PI3Kg/d inhibitors with molecules capable of inhibiting IDO1 activity may increase the rate of success of immunotherapy in PDA. By employing appropriate orthotopically injected PDA mouse models, this project aims to i) investigate the mechanisms of action of the PI3Kg/d-IDO1 axis in the control of immune suppression in PDA; ii) select in vitro the more effective combination between PI3Kg/d and IDO1 inhibitors to unleash the immune response to PDA; iii) assess the in vivo effectiveness of the selected PI3Kg/d-IDO1 inhibitors to potentiate anti-tumor effect of therapeutic combination of DNA vaccination; iv)correlate peripheral and infiltrating immune cell subsets and the expression of IDO1 and PI3Kg/d with clinical parameters and response to therapy in mouse model. The accomplishment of this research project will provide information that will impact PDA clinical management and lead to the definition of novel immunotherapy protocol to be easily transferred to the clinical practice.