Department of Hematology/Oncology, Eberhard Karls University, D-72076 Tuebingen, Germany.
J Immunol. 2012 Jul 1;189(1):154-60. doi: 10.4049/jimmunol.1103194. Epub 2012 May 30.
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.
血小板减少症抑制肿瘤生长，尤其是抑制小鼠的转移，而额外耗竭 NK 细胞则会逆转这种抗转移表型。因此，有人推测血小板可能保护血源播散的肿瘤细胞免受 NK 依赖性抗肿瘤免疫。肿瘤细胞并非单独通过血液传播，而是迅速被血小板包裹，这种现象被认为可以保护播散的肿瘤细胞免受 NK 介导的裂解。然而，其潜在机制在很大程度上仍不清楚。在这项研究中，我们表明巨核细胞在分化过程中获得了 TNF 家族成员糖皮质激素诱导的 TNF 相关配体（GITRL）的表达，从而导致血小板表达 GITRL。血小板激活后，GITRL 与α颗粒激活标志物 P-选择素一起在血小板表面上调。GITRL 也可以在与肿瘤细胞相互作用后迅速动员到血小板表面，导致血小板包裹。尽管 GITRL 与其他几个 TNF 家族成员一样能够传递反向信号，但在 GITRL 触发时，并未观察到对血小板激活和功能的影响。然而，肿瘤细胞的血小板包裹抑制了 NK 细胞的细胞毒性和 IFN-γ的产生，而通过阻断 NK 细胞上的 GITR 可以部分恢复，这表明血小板衍生的 GITRL 通过 GITR 介导 NK 抑制性正向信号。这些数据表明，血小板通过赋予肿瘤细胞 GITRL 伪表达，成为改变肿瘤细胞免疫原性的一种机制。我们的数据因此进一步证明了血小板在促进肿瘤细胞逃避 NK 细胞免疫监视中的作用。
