Heparanase is a regulator of natural killer cell activation and cytotoxicity

Heparanase is the only mammalian enzyme capable of cleaving heparan sulfate, a glycosaminoglycan of the extracellular matrix and cell surfaces. Most immune cells express heparanase that contributes to a range of functions including cell migration and cytokine expression. Heparanase also promotes natural killer (NK) cell migration; however, its role in other NK cell functions remains to be defined. In this study, heparanase-deficient (Hpse^-/- ) mice were used to assess the role of heparanase in NK cell cytotoxicity, activation, and cytokine production. Upon challenge with the immunostimulant polyinosinic:polycytidylic acid (poly(I:C)), NK cells isolated from Hpse^-/- mice displayed impaired cytotoxicity against EO771.LMB cells and reduced levels of activation markers CD69 and NKG2D. However, in vitro cytokine stimulation of wild-type and Hpse^-/- NK cells resulted in similar CD69 and NKG2D expression, suggesting the impaired NK cell activation in Hpse^-/- mice results from elements within the in vivo niche. NK cells are activated in vivo by dendritic cells (DCs) in response to poly(I:C). Poly(I:C)-stimulated Hpse^-/- bone marrow DCs (BMDCs) expressed less IL-12, and when cultured with Hpse^-/- NK cells, less MCP-1 mRNA and protein was detected. Although cell-cell contact is important for DC-mediated NK cell activation, co-cultures of Hpse^-/- BMDCs and NK cells showed similar levels of contact to wild-type cells, suggesting heparanase contributes to NK cell activation independently of cell-cell contact with DCs. These observations define a role for heparanase in NK cell cytotoxicity and activation and have important implications for how heparanase inhibitors currently in clinical trials for metastatic cancer may impact NK cell immunosurveillance.