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Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance

Abstract

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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Fig. 1: Mitochondrial fragmentation in TINK cells.
Fig. 2: Hypoxia induces mitochondrial fragmentation in NK cells.
Fig. 3: Hypoxia causes mitochondrial fragmentation by enhancing the constitutive activation of mTOR-Drp1 signaling.
Fig. 4: Mitochondrial fragmentation affects TINK cell survival.
Fig. 5: Aberrant mitochondrial metabolism is correlated with mitochondrial fragmentation in TINK cells.
Fig. 6: Restoration of the mitochondrial metabolism of TINK cells contributes to an increased antitumor capacity.

Data availability

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 13. 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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Acknowledgements

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).

Author information

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Authors

Contributions

H.W., Z.T. and X.Z. conceived and conducted the project. H.W. supervised the project. X.Z. and H.W. wrote the paper. X.Z. performed the experiments and data analysis. D.J. contributed to the cell culture and mouse models. Y.Q., P.C., Y.S. and Y.J. collected tissue samples and information from patients. R.S. and B.F. contributed to the imaging analysis and interpreted the data. H.Z. performed the hypoxic experiments.

Corresponding authors

Correspondence to Zhigang Tian or Haiming Wei.

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The authors declare no competing interests.

Additional information

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.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–6 and Supplementary Tables 1–5.

Reporting Summary

Supplementary Video 1

Mitochondrial dynamics of live hypoxic NK cells from donor 54 during 120 min of filming.

Supplementary Video 2

Mitochondrial dynamics of live hypoxic NK cells from donor 55 during 120 min of filming.

Supplementary Video 3

Mitochondrial dynamics of live hypoxic NK cells from donor 56 during 120 min of filming.

Supplementary Video 4

Mitochondrial dynamics of live normal NK cells from donor 54 during 120 min of filming.

Supplementary Video 5

Mitochondrial dynamics of live normal NK cells from donor 55 during 120 min of filming.

Supplementary Video 6

Mitochondrial dynamics of live normal NK cells from donor 56 during 120 min of filming.

Source data

Source Data Fig. 1

Unprocessed versions of the western blots shown in Fig, 3

Source Data Fig. 2

Unprocessed versions of the western blots shown in Supplementary Fig. 3

Source Data Fig. 3

Unprocessed versions of the western blots shown in Supplementary Fig. 4

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Zheng, X., Qian, Y., Fu, B. et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol 20, 1656–1667 (2019). https://doi.org/10.1038/s41590-019-0511-1

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