GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

Abstract

Thrombocytopenia inhibits tumor growth and especially metastasis in mice, whereas additional depletion of NK cells reverts this antimetastatic phenotype. It has therefore been speculated that platelets may protect hematogenously disseminating tumor cells from NK-dependent antitumor immunity. Tumor cells do not travel through the blood alone, but are rapidly coated by platelets, and this phenomenon has been proposed to shield disseminating tumor cells from NK-mediated lysis. However, the underlying mechanisms remain largely unclear. In this study, we show that megakaryocytes acquire expression of the TNF family member glucocorticoid-induced TNF-related ligand (GITRL) during differentiation, resulting in GITRL expression by platelets. Upon platelet activation, GITRL is upregulated on the platelet surface in parallel with the α-granular activation marker P-selectin. GITRL is also rapidly mobilized to the platelet surface following interaction with tumor cells, which results in platelet coating. Whereas GITRL, in the fashion of several other TNF family members, is capable of transducing reverse signals, no influence on platelet activation and function was observed upon GITRL triggering. However, platelet coating of tumor cells inhibited NK cell cytotoxicity and IFN-γ production that could partially be restored by blocking GITR on NK cells, thus indicating that platelet-derived GITRL mediates NK-inhibitory forward signaling via GITR. These data identify conferment of GITRL pseudoexpression to tumor cells by platelets as a mechanism by which platelets may alter tumor cell immunogenicity. Our data thus provide further evidence for the involvement of platelets in facilitating evasion of tumor cells from NK cell immune surveillance.

The role of platelets in the tumor microenvironment: From solid tumors to leukemia

“…A number of studies over the last fifteen years have clearly established that platelets protect tumor cells from natural killer (NK) cell-mediated lysis [23,[64][65][66][67]. Initial studies demonstrated that platelet-coated tumor cells were physically shielded from lysis by NKs [23], and this protection was not a result of passive agglutination but required platelet activation [64].…”

“…Upon aggregation by tumor cells or physiological factors, platelets mobilize to their surface membrane glucocorticoid-induced TNF-related ligand (GITRL), a member of the TNF receptor superfamily and NK-inhibitory ligand[67]. Consequently, platelet-coated tumor cells are protected, in part, from NK lytic activity and IFN- secretion due to platelet GITRL interaction with its receptor GITR on NK depletion, and likely occurred as a result of platelet sequestration and ultimately secretion from -granules of tumor-derived factors that regulate bone metabolism such as TGF-1 and MMP-1.…”

NK cells and cancer: you can teach innate cells new tricks

“…Several other mechanisms that enable tumours to evade NK cell-mediated surveillance have been documented. For example, tumours that activate platelets can avoid NK cell recognition, either directly by disrupting activating ligand expression 75 and displaying ligands for NK cell inhibitory receptors 76,77 , or indirectly by releasing immunoregulatory factors, such as transforming growth factor-β (TGFβ) 78 (FIG. 2).…”

Systemic Immune-Inflammation Index Predicts Prognosis of Patients after Curative Resection for Hepatocellular Carcinoma

“…Several studies have shown that platelets can protect CTCs from shear stresses during circulation, induce CTC epithelial-mesenchymal transition, and promote tumor cell extravasation to metastatic sites (7)(8)(9)(10). Neutrophils can promote adhesion and seeding of distant organ sites through secretion of circulating growth factors such as VEGF and proteases (11)(12)(13)(14)(15).…”