Maurer Stefanie, Kropp Korbinian Nepomuk, Klein Gerd, Steinle Alexander, Haen Sebastian P, Walz Juliane S, Hinterleitner Clemens, Märklin Melanie, Kopp Hans-Georg, Salih Helmut Rainer
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tuebingen, Germany.
Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
Oncoimmunology. 2017 Nov 27;7(2):e1364827. doi: 10.1080/2162402X.2017.1364827. eCollection 2018.
Platelets promote metastasis, among others by coating cancer cells traveling through the blood, which results in protection from NK cell immune-surveillance. The underlying mechanisms, however, remain to be fully elucidated. Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls. Platelet-mediated NKG2DL-shedding in turn resulted in impaired "induced self" recognition by NK cells as revealed by diminished NKG2D-dependent lysis of tumor cells. Our results indicate that platelet-mediated NKG2DL-shedding may be involved in immune-evasion of (metastasizing) tumor cells from NK cell reactivity.
血小板可促进转移，其中一种方式是包裹在血液中循环的癌细胞，从而使其免受自然杀伤（NK）细胞的免疫监视。然而，其潜在机制仍有待充分阐明。在此，我们报告血小板包裹会降低肿瘤细胞表面NKG2D配体的表达，尤其是MICA和MICB，这表现为它们可溶性胞外域的释放增加。将肿瘤细胞暴露于血小板释放物后也得到了类似结果，这可归因于金属蛋白酶解聚素和金属蛋白酶10（ADAM10）和金属蛋白酶解聚素和金属蛋白酶17（ADAM17），在激活后可在血小板表面和释放物中检测到它们，与健康对照相比，在转移性肺癌患者的血小板中其水平更高。血小板介导的NKG2D配体脱落进而导致NK细胞对“诱导性自身”的识别受损，这表现为肿瘤细胞的NKG2D依赖性裂解减少。我们的结果表明，血小板介导的NKG2D配体脱落可能参与了（转移性）肿瘤细胞逃避NK细胞反应的免疫逃逸过程。
