The role of natural killer cells in pancreatic ductal adenocarcinoma

Natural Killers are innate immune cells, actively involved in the detection and killing of malignant cells. Their role in pancreatic cancer is not yet understood, in part because of the paucity of infiltrative cells, compared other immune cells. Here, we have demonstrated that circulating NK cells undergo phenotypic changes, leading to functional impairment, characterised by downregulation of the main activating receptors, such as DNAM-1, NKG2D, NKp30 and NKp46. However, they retain ADCC ability and show a mature phenotype. Moreover, the analysis of the cytokines production indicates a shift to a more suppressive phenotype, highlighted by the expression of the suppressive cytokine IL-10. These changes are even more emphasized in the infiltrative compartment, with the almost complete loss of ADCC ability and the acquirement of a more “regulatory” phenotype, similar to decidual NK cells during early phases of pregnancy. Our results suggest that this could be partially induced by tumour cells, through the release of soluble form of ligands and/or the chronic cell-to-cell contact. Nevertheless, pancreatic cancer is potentially a target for NK cells’ killing activity, as demonstrated by the expression of activating ligands. In conclusion, NK cells actively participate in shaping the immune response against pancreatic cancer and they could be exploited either as a target in immune therapy and/or as biomarkers to better stratify patients, in a patient-tailored treatment settlement