NK Cells in the Tumor Microenvironment Have Fragmented Mitochondria

Natural killer cells play a crucial role in tumor immunosurveillance, and their survival has high metabolic requirements. Using transmission electron microscopy and confocal laser scanning microscopy, Zheng and colleagues found that tumor-infiltrating natural killer (TINK) cells from patients with liver cancer had fragmented mitochondria and increased levels of mitochondrial reactive oxygen species compared to normal liver natural killer cells and peripheral natural killer cells. The observed fragmentation appeared to result from the hypoxia characteristic of the tumor microenvironment; specifically, the fragmentation was caused by hypoxia-induced constitutive activation of mTOR–DRP1 signaling. Mitochondrial fragmentation was correlated with TINK-cell apoptosis and aberrant mitochondrial metabolism in TINK cells, and restoration of normal mitochondrial morphology was associated with antitumor activity of NK cells. Experiments using a mouse model of hepatocellular carcinoma treated with a small-molecule inhibitor of mitochondrial fission implied that mitochondrial fragmentation was related to decreased antitumor activity of NK cells. Together, these results support mitochondrial fragmentation induced by hypoxia in the tumor microenvironment as a previously unrecognized mechanism by which tumors may escape immune suppression. Further, investigation of DRP1 inhibitors that restore normal mitochondrial function to NK cells may be worth investigating as therapeutics.

Zheng X, Qian Y, Fu B, Jiao D, Jiang Y, Chen P, et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol 2019 Oct 21 [Epub ahead of print].

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