Natural killer (NK) cells have crucial roles in tumor surveillance. We found that tumor-infiltrating NK cells in human liver cancers had small, fragmented mitochondria in their cytoplasm, whereas liver NK cells outside tumors, as well as peripheral NK cells, had normal large, tubular mitochondria. This fragmentation was correlated with reduced cytotoxicity and NK cell loss, resulting in tumor evasion of NK cell-mediated surveillance, which predicted poor survival in patients with liver cancer. The hypoxic tumor microenvironment drove the sustained activation of mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) in NK cells, resulting in excessive mitochondrial fission into fragments. Inhibition of mitochondrial fragmentation improved mitochondrial metabolism, survival and the antitumor capacity of NK cells. These data reveal a mechanism of immune escape that might be targetable and could invigorate NK cell-based cancer treatments.
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Microarray data were deposited into the National Center for Biotechnology Information Gene Expression Omnibus repository (accession number: GSE120123). The clinical characteristics of all patients included in the present study are shown in Supplementary Tables 1–3. All gene sets are shown in Supplementary Table 4. The antibodies used are shown in Supplementary Table 5. Full scans of all of the blots and gels are included in the Source Data. The data that support the findings of this study are available from the corresponding author upon request.
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We thank W. Tao for advice regarding RNA sequencing data analyses. This work was supported by the Natural Science Foundation of China (reference numbers 81330071, 81788101, 81872318 and 81602491) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB1002 and XDA12020217).
The authors declare no competing interests.
Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–6 and Supplementary Tables 1–5.
Mitochondrial dynamics of live hypoxic NK cells from donor 54 during 120 min of filming.
Mitochondrial dynamics of live hypoxic NK cells from donor 55 during 120 min of filming.
Mitochondrial dynamics of live hypoxic NK cells from donor 56 during 120 min of filming.
Mitochondrial dynamics of live normal NK cells from donor 54 during 120 min of filming.
Mitochondrial dynamics of live normal NK cells from donor 55 during 120 min of filming.
Mitochondrial dynamics of live normal NK cells from donor 56 during 120 min of filming.
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Zheng, X., Qian, Y., Fu, B. et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol (2019) doi:10.1038/s41590-019-0511-1
Nature Immunology (2019)