J Immunol：血小板减少后抑制肿瘤转移

血小板与肿瘤细胞相互作用形成癌栓是肿瘤细胞发生转移和远端定位的关键血小板可以在以下方面利于肿瘤的血行转移：1）与肿瘤细胞形成癌栓保护层而与免疫防御系统隔离，有利于肿瘤细胞在循环运输过程的存活；2）使肿瘤细胞成功地抵御了血流的高剪切力的损伤而存活在血液中，从而保护肿瘤细胞免受机体防御机制的清除。

在小鼠体内血小板数目的减少能抑制肿瘤的生长，尤其对抑制肿瘤转移来说非常有效，而NK细胞的缺失却会逆转血小板的这种抗转移潜能。因此，早期研究人员推测血小板可保护肿瘤细胞在血行转移过程中免受NK细胞的抗肿瘤免疫杀伤作用。

肿瘤细胞并不是作为个体在血流中传播，肿瘤细胞会与血小板粘附在一起形成癌栓。癌栓的形成一方面保护了肿瘤细胞免受NK细胞的杀伤，同时也避免肿瘤细胞免受血流切力的破坏。然而，其中的基本机制仍不清楚。

近日发表在Journal of Immunology杂志上的一则研究中，研究人员证实巨核细胞分化过程中可获得表达TNF家族成员糖皮质激素诱导的肿瘤坏死因子相关配体（GITRL），最终造成血小板表达GITR。血小板活化后，血小板表面α-颗粒活化标志物P-选择素上调GITRL。

GITRL也迅速动员血小板表面的粘附分子与肿瘤细胞相互作用，导致血小板包被住肿瘤细胞。而其他几个TNF家族成员，有能力反向转导信号，让血小板接受GITRL触发时其活化和功能不会发生变化。然而，肿瘤细胞与血小板之间的癌栓抑制NK细胞毒性，减少γ-干扰素生产的这两个作用可通过阻断NK细胞上GITR的活性被部分恢复，从而表明血小板衍生GITRL通过GITR介导NK细胞抑制前馈信号。研究数据为进一步阐明了血小板是如何参与NK细胞免疫监视肿瘤细胞的过程。

doi:10.4049/jimmunol.1103194
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GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

Theresa Placke, Helmut R. Salih and Hans-Georg Kopp

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.