Periodic Reporting for period 3 - X-TAM (Dissecting Cross-Regulatory Interplays in Tumor-Associated Macrophages) Reporting period: 2021-03-01 to 2022-08-31 Summary of the context and overall objectives of the project Pancreatic cancer is one of the most aggressive forms of tumors, for which limited therapeutic options are available. The characterization of pathogenetic events in pancreatic cancer progression and the identification of novel therapeutic targets remain fundamental objectives in oncology. In this context, there is evidence that pancreatic cancer can subdue the host immune system by reprogramming the activity of a type of immune cells called macrophages. This project aims at determining how pancreatic cancer interact with tumor-associated macrophages. Identification of and targeting of this interplay may lead to novel therapeutic strategies boosting anti-tumor immunity for the treatment of this disease. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Using cutting-edge genomic technologies, we have performed a comprehensive analysis of the molecular alterations occurring in cells of the immune system upon infiltration into pancreatic tumors. These data have revealed a unique molecular blueprint of tumor-associated macrophages that is associated to disease progression and poor prognosis. We have found that pancreatic cancer cells produce a class of molecules able to convert macrophages from activators to suppressors of anti-tumor immunity. In preliminary experiments, targeting these molecules was associated to reduced tumor growth and higher immune-mediated tumor rejection in preclinical models of pancreatic cancer. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) This project combines innovative genomic technologies with advanced bioinformatic analyses to uncover novel drivers of pancreatic cancer progression and regulators of the interplay with the immune system. Data obtained so far have uncovered a novel therapeutic target, giving us mandate to explore the efficacy of targeting tumor-associated macrophages in this disease. If successful, this project may inform the development, preclinical validation and ultimately clinical testing of novel therapeutic strategies for pancreatic cancer.