Extracellular Proliferating Cell Nuclear Antigen is a novel marker for cancer stem cells and facilitates evasion of Natural Killer cell effector function (P2133)

Abstract

Natural Killer (NK) cell function is strictly regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. NKp44, originally discovered as an activating NK cell receptor, was recently found to elicit inhibitory effects on NK cell effector function through recognition of cell surface Proliferation Cell Nuclear Antigen (PCNA). Other reports have pointed to potential associations between NKp44 and Human Leukocyte Antigen (HLA) I molecules. In this report, we have identified novel interactions between HLA I and PCNA on the surface of human tumor cells by confocal microscopy and immunoprecipitation. In addition to previous reports, we show PCNA on the cell surface where novel association with HLA I does not require the presence of NKp44 expressing NK cells and occurs with endogenous PCNA. The association of HLA I and PCNA forms the inhibitory ligand for NKp44, resulting in inhibition of NK effector function. Furthermore, extracellular PCNA was only found on tumor cells exhibiting a cancer stem cell phenotype. Thus extracellular PCNA is a novel marker for cancer stem cells, derived from conventional growth of tumor epithelial cell lines in tissue culture, and a mechanism by which cancer stem cells evade NK cell effector functions.