The Antitumor Effect of Heparin is not Mediated by Direct NK Cell Activation

Abstract

Natural killer (NK) cells are innate lymphocytes responsible for the elimination of infected or transformed cells. The activation or inhibition of NK cells is determined by the balance of target cell ligand recognition by stimulatory and inhibitory receptors on their surface. Previous reports have suggested that the glycosaminoglycan heparin is a ligand for the natural cytotoxicity receptors NKp30, NKp44 (human), and NKp46 (both human and mouse). However, the effects of heparin on NK cell homeostasis and function remain unclear. Here, we show that heparin does not enhance NK cell proliferation or killing through NK cell activation. Alternatively, in mice models, heparin promoted NK cell survival in vitro and controlled B16-F10 melanoma metastasis development in vivo. In human NK cells, heparin promisingly increased interferon (IFN)-γ production in synergy with IL-12, although the mechanism remains elusive. Our data showed that heparin is not able to increase NK cell cytotoxicity.

Heparin and Heparin-Based Drug Delivery Systems: Pleiotropic Molecular Effects at Multiple Drug Resistance of Osteosarcoma and Immune Cells

“…Moreover, heparin restores hIL-12 signaling in a natural killer cell line (NK-92MI) in which both IL-12 receptor subunits, IL-12Rβ1 and IL-12Rβ2, were functionally deleted [ 245 ]. Heparin is believed to be a ligand for the natural cytotoxicity receptors NKp30, NKp44 (human), NKp46 (human and mouse) [ 246 ]. At the same time, heparin is not able to increase the cytotoxicity of NK cells [ 246 ].…”

“…Heparin is believed to be a ligand for the natural cytotoxicity receptors NKp30, NKp44 (human), NKp46 (human and mouse) [ 246 ]. At the same time, heparin is not able to increase the cytotoxicity of NK cells [ 246 ].…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…This unanticipated result may be due to the lack of other cells that contribute to the cell response. A recent report reveals that the effect of heparin as the antitumor drug does not involve NK cell activation, suggesting that heparin instead activates Th1 and hence NK cells are more cytotoxic against the tumour [118]. More research is required to ascertain the importance of this drug on in vivo NK cell modulation in pregnancy.…”

“…Patients with antiphospholipid antibodies and with thrombotic pathologies are treated with heparin during pregnancy. There are several hypotheses on the possible mechanisms of heparin; however, none of them involved NK cell response [118,119]. Thus, heparin's role in preventing thrombotic events may be crucial for the embryo or fetal survival.…”

“…Thus, heparin's role in preventing thrombotic events may be crucial for the embryo or fetal survival. The use of heparin as an immunomodulator is complicated to envision; however, the effect of heparin binding to receptors on different cell types and modulating cellular processes may, in turn, affect NK cell response [118,119]. Therefore, more research should be performed to ascertain the possible effect of this and other glycosaminoglycans on NK cell function.…”