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.