Functional visualization of NK cell-mediated killing of metastatic single tumor cells

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 unknown. Here, we have combined ultra-sensitive bioluminescence 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 hr of arrival, but not thereafter. Intravital dynamic imaging revealed that 50% of NK-tumor cell encounters lead to tumor cell death in the first 4 hr after tumor cell arrival, but after 24 hr of arrival, nearly 100% of the interactions result in the survival of the tumor cell. During this 24-hr period, the probability of ERK activation in NK cells upon encountering the tumor cells was decreased from 68% to 8%, which correlated with the loss of the activating ligand CD155/PVR/Necl5 from the tumor cell surface. Thus, by quantitatively visualizing, the NK-tumor cell interaction at the early stage of metastasis, we have revealed the crucial parameters of NK cell immune surveillance in the lung.

Automated summary

NK cells play a crucial role in limiting metastatic growth in the lung, but some cancers can evade their immune surveillance mechanisms. By combining bioluminescence imaging and two-photon microscopy, researchers have found that NK cells can eliminate disseminated tumor cells from the lung within 24 hours, but their effectiveness decreases after that time. The study also revealed that the loss of the activating ligand CD155/PVR/Necl5 from tumor cells contributes to their survival after 24 hours.