Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is not known. Here we have combined ultra-sensitive bioluminescence whole body imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that a disseminated tumor cell in a pulmonary capillary interacts with an NK cell every 2 hrs on average. In the first 4 hrs after tumor cell arrival, 50% of such encounters lead to tumor cell death but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. This evasion of NK cell surveillance is mediated by thrombin-dependent loss of cell surface CD155/PVR/Necl-5, a ligand for the NK cell activating receptor DNAM-1. This loss prevents the NK cell signaling needed for effective killing of tumor targets. By quantitatively visualizing the evasion of NK cell surveillance, we have uncovered a molecular mechanism for cancer evasion and provided an explanation for the anti-metastatic effect of anticoagulants.

中文翻译：

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转移性单个肿瘤细胞通过凝血酶介导的活化配体CD155 / PVR / Necl-5的凝血酶损失而逃避NK细胞介导的杀伤。

天然杀伤（NK）细胞裂解入侵的肿瘤细胞以限制肺中的转移性生长，但是尚不清楚某些癌症如何逃避这种宿主保护机制以建立生长的病变。在这里，我们将超灵敏的生物发光全身成像与活体两光子显微镜相结合，涉及基因编码的生物传感器，以研究这一问题。NK细胞在到达后24小时内从肺中清除了已扩散的肿瘤细胞，但此后没有。活体内动态成像显示，平均每2小时，肺毛细血管中已扩散的肿瘤细胞与NK细胞相互作用。在肿瘤细胞到达后的最初4小时内，有50％的此类相遇导致肿瘤细胞死亡，但在到达肿瘤细胞24小时后，几乎100％的相互作用导致肿瘤细胞存活。NK细胞监视的这种逃避是由凝血酶依赖性细胞表面CD155 / PVR / Necl-5（NK细胞活化受体DNAM-1的配体）依赖性损失介导的。这种损失阻止了有效杀死肿瘤靶标所需的NK细胞信号传导。通过定量可视化NK细胞监视的逃避，我们发现了逃避癌症的分子机制，并为抗凝剂的抗转移作用提供了解释。