Multiple defects in NK cells of surgically resectable pancreatic cancer patients can be reversed by ex-vivo stimulation

Abstract

Abstract Tumor infiltrating lymphocytes (TILs) are found in advanced pancreatic ductal adenocarcinoma (PDAC) patients and shown to correlate with overall survival (OS) rate. Although majority of TILs consisted of CD8+/CD4+T cells, the presence of NK cells and their role in the pathogenesis of PDAC remains elusive. We performed comprehensive analyses of TIL and PBMC to explore the role of NK cells in the newly developed PDAC patients. Multiple defects in cell migration and effector function were observed in NK cells of patients’ peripheral blood. Extremely low frequencies of NK cells (<0.5%) were found in TILs of PDAC patients which was attributable not to low expression of tumor chemokines, but rather lack of the CXCR2 chemokine receptor. Forced expression of CXCR2 on patients’ NK cells rendered them capable of trafficking PDAC tumors. Furthermore, patients’ NK cells exhibited impaired cell-mediated killing against autologous PDAC tumor cells and failed to proliferate within hypoxic tumor microenvironment. Importantly, these defects can be overcome by ex-vivo activation of NK cells from PDAC patients. When the proliferative capacity of NK cells in vitro was used to stratify patients on the basis of cell expansion, a clear difference in DFS and OS was observed. Patients whose NK cells proliferated <250 fold experienced significantly lower DFS and OS than those expanded ≥250 fold. Multiple defects are observed in NK cells of PDAC patients. Ex-vivo activation of NK cells restores tumor reactivity and provides a therapeutic modality while their fold expansion can be a potentially significant prognostic indicator of OS and DFS in PDAC patients.