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Jan 17, 2021

Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5

  • Hiroshi Ichise
  • Shoko Tsukamoto
  • Tsuyoshi Hirashima
  • Yoshinobu Konishi
  • Choji Oki
  • Shinya Tsukiji
  • Satoshi Iwano
  • Atsushi Miyawaki
  • Kenta Sumiyama
  • Kenta Terai
  • Michiyuki Matsuda
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DOI
10.1101/2021.01.15.426784
Publisher
Cold Spring Harbor Laboratory

<title>ABSTRACT</title>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.

<sec><title>SUMMARY</title>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.

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Link information
DOI
https://doi.org/10.1101/2021.01.15.426784
URL
https://syndication.highwire.org/content/doi/10.1101/2021.01.15.426784
ID information
  • DOI : 10.1101/2021.01.15.426784

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