Natural killer cells (NK cells) are a kind of effector lymphocytes, which play an important role in the anti-tumor process of human body. However, some tumor cells could escape the attack of NK cells with gradually invasion and transformation, and would seriously endanger human health. Its mechanism needs further study.
Prof. WEI Haiming and TIAN Zhigang from University of Science and Technology of China, in cooperation with Director QIAN Yeben from the First Affiliated Hospital of Anhui Medical University, found that the mitochondria of NK cells in liver cancer broke and their anti-tumor function was lost. The research was published online in Nature Immunology on October 21st, 2019, under the title of Mitochondrial Fragmentation Limits NK Cell Based Tumor Immunity. This study revealed a new mechanism of tumor immune escape, and provided new ideas and targets for tumor immunotherapy based on NK cells.
Mitochondrion is the center of cell metabolism, its morphology is highly dynamic, and it continuously fuses and divides. After mitochondrion fusion, it is linear or tubular, and its respiration and oxidative phosphorylation are strengthened. It could also interact with endoplasmic reticulum to improve the flow of calcium ions and play a normal function of cells. After mitosis, ROS production, apoptosis and autophagy would be accelerated, which will seriously interfere with the normal function of cells.
The mitochondria of normal NK cells were tubular (left, green), while those of tumor infiltrated NK cells were fragmented (right, green), image provided by ZHENG Xiaohu, artistic processing by WANG Guoyan and CHEN Lei.
By using transmission electron microscopy, researchers could clearly see the significant difference between normal and tumor infiltrated NK cells. The normal NK cell’s mitochondria is tubular and large, while the one of tumor infiltrated NK cell is fragmented and small. Further study on its mechanism showed that the hypoxia state of tumor microenvironment was an important reason for inducing mitochondrial rupture of NK cells; hypoxia could continuously activate mTOR-Drp1 signal of NK cells in tumor microenvironment, leading to excessive mitosis of mitochondria, resulting in decreased NK cell’s activity and tumor killing ability. In the patients with liver cancer, the more serious the local hypoxia is, the less the number of NK infiltrated cells in tumor tissue is, which tends to be cold tumor, and the survival period of patients is worse. After pretreatment with mTOR or Drp1 inhibitors, the mitochondrial morphology and respiratory effect of NK cells in tumor microenvironment were significantly improved, and the tumor killing ability was also enhanced.
This study explains the new mechanism of tumor derived NK cells' function disorder and immune escape from the perspective of metabolism, and provides a new strategy for improving the immunotherapy of NK cells.
National Natural Science Foundation and Chinese Academy of Sciences supported the research.