Clinical Relevance of Immune Cells in Pancreatic Adenocarcinoma and their Implication in Immunotherapy

This thesis summarizes the work I have done during my PhD training, focused on the immune microenvironment of pancreatic adenocarcinoma (PDAC). The aim was to delineate key features of immunologic and tumour components shaping the biology of pancreatic cancer. Immunotherapy has been largely explored as a promising anticancer approach but not convincingly introduced yet for this tumour type. The results here summarized could contribute to a better understanding of the microenvironment of human PDAC and foster the introduction of immunotherapeutic strategies into the clinical practice. The first section of the thesis summarizes the work done to investigate the occurrence of tertiary lymphoid tissue (TLT) in PDAC. TLT has been demonstrated to coordinate the recruitment and activation of adaptive immune cells in several tumour settings. This work documents the occurrence of TLT in pancreatic cancer, addresses the prognostic role of B cells according to their spatial distribution within TLT and tests the hypothesis that TLT can serve as immunological sites that contribute to efficacy of immunotherapeutic vaccination. The second section is focused on the intersection between cancer metabolism and immune function in PDAC. In order to unearth early metabolic alterations in PDAC, we have analyzed the pancreatic juice, a relatively unexplored liquid biopsy potentially enriched with tumor-derived metabolites. Our results indicate a specific metabolic signature that allows to single out PDAC from other pancreatic pathologies and reveal an important link between glucose metabolism and accumulation of PD-1+ cells in PDAC tumors.