Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance

Zheng, Xiaohu; Qian, Yeben; Fu, Binqing; Jiao, Defeng; Jiang, Yong; Chen, Peng; Shen, Yiqing; Zhang, Huafeng; Sun, Rui; Tian, Zhigang; Wei, Haiming

doi:10.1038/s41590-019-0511-1

Cited by 183 publications

(165 citation statements)

References 48 publications

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“…Pharmacological inhibition of mTOR by rapamycin reduces the upregulation of glycolysis in mouse NK cells stimulated by IL-2/IL-12, and leads to a decrease in mitochondrial mass and membrane potential in human NK cells stimulated by IL-2, resulting in impaired effector functions ( 36 , 55 ). Consistently, CD56 bright NK cells that exhibit stronger metabolic responses to IL-2 or IL-12/IL-15 stimulation, have higher mTOR activity compared with CD56 dim NK cells ( 40 ); however, excessive activation of mTOR can cause mitochondrial fragmentation, thereby damaging mitochondrial function ( 37 ).…”

Section: Basic Nk Cell Metabolismmentioning

confidence: 98%

“…They found that tumor NK cells had small, fragmented mitochondria in patients with liver cancer, which was a consequence of hypoxia-induced excessive mitochondrial fission. This mitochondrial fragmentation impaired the cytotoxicity and survival of NK cells, thereby resulting in immune evasion ( 37 ).…”

Section: Nk Cell Metabolism In Diseasementioning

confidence: 99%

“…Inhibiting PPAR or blocking lipid transport into mitochondria restores NK cell cytotoxicity during obesity, which might improve cancer outcomes in such patients ( 35 ). Tumor-induced FBP1 and mitochondrial fragmentation account for impaired NK cell anti-tumor functions by compromising glycolysis and mitochondrial respiration, respectively, and targeting them can enhance NK cell-based tumor immunosurveillance ( 34 , 37 ). Dysregulation of mTOR activity is observed in diverse tumors.…”

Section: Targeting Ilc Metabolism For Therapymentioning

confidence: 99%

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Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

Cong

2020

Front. Immunol.

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Natural killer (NK) cells are the host's first line of defense against tumors and viral infections without prior sensitization. It is increasingly accepted that NK cells belong to the innate lymphoid cell (ILC) family. Other ILCs, comprising ILC1s, ILC2s, ILC3s and lymphoid tissue inducer (LTi) cells, are largely non-cytotoxic, tissue-resident cells, which function to protect local microenvironments against tissue insults and maintain homeostasis. Recently, evidence has accumulated that metabolism supports many aspects of the biology of NK cells and other ILCs, and that metabolic reprogramming regulates their development and function. Here, we outline the current understanding of ILC metabolism, and describe how metabolic processes are affected, and how metabolic defects are coupled to dysfunction of ILCs, in disease settings. Furthermore, we summarize the current and potential directions for immunotherapy involving targeting of ILC metabolism. Finally, we discuss the open questions in the rapidly expanding field of ILC metabolism.

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Section: Basic Nk Cell Metabolismmentioning

confidence: 98%

Section: Nk Cell Metabolism In Diseasementioning

confidence: 99%

Section: Targeting Ilc Metabolism For Therapymentioning

confidence: 99%

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Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

Cong

2020

Front. Immunol.

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“…The hypoxic TME induces excessive mitochondrial fission in natural killer (NK) cells. This reduces NK cell viability and immunosurveillance [88]. Tumor cell-secreted PRSS (a serine protease) not only promotes angiogenesis and cancer cell invasion but also induces resistance to monoclonal antibodies such as cetuximab and bevacizumab by cleaving them into inactive forms [89].…”

Section: Favorable Tumor Microenvironmentmentioning

confidence: 99%

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

et al. 2020

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Circular RNAs (circRNAs), one type of non-coding RNA, were initially misinterpreted as nonfunctional products of pre-mRNA mis-splicing. Currently, circRNAs have been proven to manipulate the functions of diverse molecules, including non-coding RNAs, mRNAs, DNAs and proteins, to regulate cell activities in physiology and pathology. Accumulating evidence indicates that circRNAs play critical roles in tumor genesis, development, and sensitivity to radiation and chemotherapy. Radiotherapy and chemotherapy are two primary types of intervention for most cancers, but their therapeutic efficacies are usually retarded by intrinsic and acquired resistance. Thus, it is urgent to develop new strategies to improve therapeutic responses. To achieve this, clarification of the underlying mechanisms affecting therapeutic responses in cancer is needed. This review summarizes recent progress and mechanisms of circRNAs in cancer resistance to radiation and chemotherapy, and it discusses the limitations of available knowledge and potential future directions.

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“…TGF-β and IL-10 promoted NK-cell exhaustion in HCC [22,23] . Hypoxia-induced mitochondrial fragmentation limits NKcell anticancer activity [24] . Additionally, immunosuppressive cells such as myeloid-derived suppressor cells, monocyte/macrophage, and HCC-associated fibroblasts in intratumor tissues of HCC contribute to NKcell exhaustion [25][26][27] .…”

Section: Nk Cells In Hccmentioning

confidence: 99%

Cytotoxic immune cell-based immunotherapy for hepatocellular carcinoma

Li¹,

Liu²,

Wang³

2020

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Hepatocellular carcinoma (HCC) is one of the most common solid tumors with poor clinical prognosis. Novel therapeutic regimens are urgently required for patients with advanced HCC. Both pre-clinical and clinical studies suggest immunotherapy as an attractive alternative for advanced HCC treatment. Natural killer (NK) cells and CD8 + T cells are the most important cytotoxic immune cells involved in cancer treatment and elimination. Reinvigorating the anticancer activity of NK and CD8 + T cells is the fundamental guarantee for the success of immunotherapy in advanced HCC treatment. Therefore, in this review, we aim to summarize the characteristics and roles of NK and CD8 + T cells in HCC development, describe the frontiers of immunotherapy for advanced HCC based on immune checkpoint inhibitors and adoptive cell transfer, and discuss their limitations and scope for future improvement.

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Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance

Cited by 183 publications

References 48 publications

Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

Cytotoxic immune cell-based immunotherapy for hepatocellular carcinoma

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