Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5
Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5
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DOI：
10.1101/2021.01.15.426784
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发表时间：
2021-01
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通讯作者：
H. Ichise;Shoko Tsukamoto;Tsuyoshi Hirashima;Y. Konishi;Choji Oki;S. Tsukiji;S. Iwano;A. Miyawaki;K. Sumiyama;Kenta Terai;M. Matsuda
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作者：
H. Ichise;Shoko Tsukamoto;Tsuyoshi Hirashima;Y. Konishi;Choji Oki;S. Tsukiji;S. Iwano;A. Miyawaki;K. Sumiyama;Kenta Terai;M. Matsuda
自然杀伤（NK）细胞裂解入侵的肿瘤细胞以限制肺中的转移性生长，但一些癌症如何逃避这种宿主保护机制以建立生长性病变尚不清楚。在这里，我们结合了超灵敏的生物发光全身成像与活体双光子显微镜，涉及遗传编码的生物传感器来研究这个问题。NK细胞在到达后24小时内从肺中消除了播散的肿瘤细胞，但此后没有。活体动态显像显示，肺毛细血管中的播散性肿瘤细胞平均每2小时与NK细胞相互作用一次。在肿瘤细胞到达后的前4小时内，50%的这种接触导致肿瘤细胞死亡，但在到达24小时后，几乎100%的相互作用导致肿瘤细胞存活。这种逃避NK细胞监视是由细胞表面CD 155/PVR/Necl-5（NK细胞活化受体DNAM-1的配体）的凝血酶依赖性损失介导的。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，我们揭示了癌症逃避的分子机制，并为抗凝剂的抗转移作用提供了解释。摘要活体功能性双光子显微镜显示，肺毛细血管中的转移性肿瘤细胞获得对巡逻NK细胞的抗性。蛋白酶介导的肿瘤细胞上活化配体CD 155/PVR/Necl-5的丧失可防止NK细胞活化ERK和杀伤肿瘤细胞。
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. SUMMARY Intravital functional two-photon microscopy reveals that metastatic tumor cells lodged in pulmonary capillaries acquire resistance to patrolling NK cells. Protease-mediated loss of the activating ligand CD155/PVR/Necl-5 on tumor cells prevents NK cells from ERK activation and tumor cell killing.