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.
Highlights
Immune checkpoint inhibitors have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes
natural killer (NK) cells are emerging as targets for cancer immunotherapy due to many advantages
Cancer cells create a complex tumor microenvironment to evade immunosurveillance by NK cells [10], such as using the TGF-β superfamily to impair NK cell antitumor responses by suppressing their metabolism, killing capacity, and inducing tissue residency characteristics [11,12,13]
Summary
Immune checkpoint inhibitors have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes. Aside from the inhibition of many coagulation cascade components, heparin binds to P-selectin on the surface of platelets, blocking their adhesion to tumor cells and making them more visible to the immune system [21] The combination of such factors leads to reduction of metastasis in a number of animal models, such as colon and mammary cancer, melanoma, and adenocarcinoma [22,23,24,25]. Some reports suggest a potential interaction between heparin and NK cell stimulatory receptors, such as NKp30, NKp44 (human) and NKp46 (both human and mouse) [26,27,28] Whether these interactions can lead to activation of NK cell antitumor responses is still unanswered. We investigated the hypothesis that heparin could activate NK cell antitumor responses by increasing their cytotoxic capacity against tumor cells
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