Studies have found the key mechanism by which natural killer cells lose their anti-tumor function

Natural killer cells (NK cells) are the “professional killers” of tumors and play a pivotal role in anti-tumor immunotherapy, but in the tumor microenvironment, the anti-tumor function of NK cells is seriously challenged, and most advanced tumors can escape the killing of NK cells. To this end, researchers urgently need to understand the mechanism and find a new solution to restore NK cell function.

The research group of Wei Haiming, Zheng Xiaohu and Tian Zhigang of the University of Science and Technology of China, together with the research group of Professor Huang Guangming of the School of Chemistry and Materials Science and Professor Qian Yeben of the First Affiliated Hospital of Anhui Medical University, found that NK cells in the tumor tissue microenvironment lost surface membrane protrusions, could not recognize tumor cells, and lost their anti-tumor function. They also created a “single immune cell membrane mass spectrometry detection technique” to reveal that the loss of sphingomyelin, a major component of NK cell membranes, is the main cause of NK cell loss of surface protrusions. On March 23, the results were published online in the journal Nature Immunity. The study revealed a new mechanism of tumor immune evasion, which provided new ideas and targets for NK cell-based tumor immunotherapy.

The surface of normal NK cells derived from peripheral blood and liver tissues shows abundant membrane bulges (left, middle), while the surface of NK cells in the tumor tissue microenvironment is abnormally smooth, and the membrane bulges are lost (right) Photo courtesy of China University of Science and Technology

Using transmission and scanning electron microscopy technology, the researchers can clearly see that the topological morphology of NK cell membranes in the microenvironment of normal tissues and tumor tissues is clearly different, and there are abundant protrusions on the surface of normal NK cell membranes, while the surface of NK cell membranes in the microenvironment of tumor tissues is abnormally smooth, and the protrusions are obviously lost.

Further exploration found that normal NK cells use membrane protrusions to recognize and grasp tumor cells, and promote cell-to-cell interaction to form “immune synapses” and play a tumor-killing role. This immune synapse is a special intercellular structure formed between NK cells and tumor cells, and NK cells release granzyme through immune synapses to lyse tumor cells. However, NK cell protrusions in the tumor tissue microenvironment of advanced tumor patients are lost, tumor cells cannot be recognized, and immune synapses cannot be formed, thereby losing the ability to kill tumor cells.

In addition, the researchers also created a “single immune cell membrane mass spectrometry detection technology”, which found that the membrane composition of NK cells in the tumor microenvironment changed, mainly the content of sphingomyelin, and confirmed that the dysregulation of serine metabolism in the tumor microenvironment was the main cause of the decline of sphingomyelin. The use of inhibitors targeting sphingomyelinase can significantly increase the content of sphingomyelin, restore protrusion formation, and improve tumor cell recognition and killing ability in tumor microenvironment. The intervention method targeting sphingomyelinase combined with immune checkpoint blockers has a synergistic anti-cancer effect.

The researchers believe that this study interprets the new mechanism of dysfunction and immune escape of tumor-derived NK cells from a new perspective of cell membrane topology, and also provides a new strategy for improving the immunotherapy of NK cells. (Source: Wang Min, China Science News)

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