Cancer stem cells inhibit NK cell effector function via PCNA-NKp44 interaction

Abstract

Abstract NK cells participate in the innate immune response against infection and cancer without prior sensitization. NK cell function depends on a balance of signals transmitted from activating and inhibitory receptors interacting with ligands on the surface of cells. Cancer cells may evade NK-mediated killing by expressing ligands for inhibitory receptors. Proliferating cell nuclear antigen (PCNA) associates with MHC I and forms the inhibitory ligand for NKp44, resulting in the inhibition of NK function. Cancer stem cells (CSC), a unique subset of tumor cells, possess a stem-cell-like phenotype and are thought to facilitate metastasis by escaping NK cell effector function. Pancreatic and colon CSC can be identified by co-expression of surface markers CD44 and CD133. In both cell lines, Panc-1 and HCT 116, cell surface PCNA is associated with co-expression of CD44 and CD133 as well as increased CSC transcription factor expression (NANOG, SOX2, and Oct-4). Blocking the interaction of NKp44 and PCNA enhanced the specific lysis of cells by NK cells. Collectively these data demonstrate that surface PCNA, CD44, and CD133 co-expression is a marker of pancreatic and colon CSC. Our research implicates that blocking NKp44-PCNA interaction may provide a novel immunotherapeutic target for pancreatic and colon cancer stem cells and prevent metastasis.