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Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance
Xiaohu Zheng1,2, Yeben Qian3, Binqing Fu1,2
1Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.
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.
Insights
Tumor-infiltrating natural killer (NK) cells in liver cancer exhibit fragmented mitochondria, impairing their tumor-killing ability. Targeting this mitochondrial fragmentation could enhance NK cell cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Metabolism
Background:
- Natural killer (NK) cells are critical for identifying and eliminating cancerous cells.
- Tumor microenvironments can suppress immune responses, leading to cancer progression.
- Mitochondrial function is essential for immune cell activity and survival.
Purpose of the Study:
- To investigate the role of mitochondria in the function of tumor-infiltrating NK cells in liver cancer.
- To elucidate the mechanisms behind NK cell dysfunction within the tumor microenvironment.
- To identify potential therapeutic targets for enhancing NK cell-mediated anti-tumor immunity.
Main Methods:
- Comparative analysis of mitochondria in tumor-infiltrating NK cells versus non-tumor NK cells from liver cancer patients.
- Assessment of NK cell cytotoxicity and correlation with mitochondrial morphology.
- Investigation of the mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) pathway in response to tumor hypoxia.
- Evaluation of therapeutic interventions targeting mitochondrial fragmentation.
Main Results:
- Tumor-infiltrating NK cells displayed small, fragmented mitochondria, unlike normal, tubular mitochondria in non-tumor and peripheral NK cells.
- Mitochondrial fragmentation in NK cells correlated with reduced cytotoxicity, NK cell loss, and poor patient survival.
- Hypoxia-induced mTOR-Drp1 activation in NK cells drove excessive mitochondrial fission.
- Inhibition of mitochondrial fragmentation restored NK cell metabolism, survival, and anti-tumor capacity.
Conclusions:
- Mitochondrial fragmentation is a key mechanism of immune escape in liver cancer, driven by the tumor microenvironment.
- Targeting mitochondrial dynamics in NK cells presents a promising strategy to overcome immune suppression.
- Restoring NK cell mitochondrial health can enhance their anti-tumor efficacy and improve cancer treatment outcomes.
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