Introduction: The advent of cancer immunotherapy has once reversed the deadlock in previous cancer treatment, and has been recognized by many scientists. However, with the popularization of cancer immunotherapy, more and more disadvantages are gradually revealed. Take CAR-T therapy, for example, tumor cell targets have not been completely broken. At present, the surface-specific antigen protein of all cancer cells, which is what we call a target, has not been fully grasped. If we want to use CAR-T to treat more types of cancer in the future, we must constantly find new targets. Secondly, CAR-T cells still have some risks, such as cytokine storm and neurotoxicity. Last but not least, the current breakthrough in cancer immunotherapy: there is a huge difference in treatment response between cancer patients.
Recently, scientists from University College London and Peter McCarran Cancer Centre have finally made a breakthrough in this field: they found that white blood cells release toxic proteins to kill cancer cells and virus-infected cells, unlike chemotherapy. The enemy one thousand and eighty damage themselves, they use the physical characteristics of their own cell envelope to protect themselves from any harm. This largely explains the difference in the response of cancer patients to cancer immunotherapy, and related articles have been published online in Nature communications.
Cancer immune cell therapy is to take the immune cells fighting cancer cells and viruses and other foreign bodies from the patient's blood from our body, increase the number of cultured in the laboratory, return to the body, restore the patient's immune strength and attack the tumor Treatment.
After the onset of cancer, the human body fights mainly through the third line of defense, which plays a role in various types of immune cells. Cytotoxic T lymphocytes (CTL cells) are the main force of T cells, killing cancer cells to be neat and neat. These types of cells carry a molecular marker of CD3 + CD8 +. They can directly attack cells that are "attached" by the pathogen or mutated cancer cells. After checking the cell ID "MHC protein", they will not hesitate It secretes "perforin" and "granulase", which can pass directly through the cell's body (cell membrane), causing the cell to lyse and die.
Although both CTL and target cells are exposed to perforin within the synapse, only the target cell membrane is destroyed, and CTL escapes without exception. This has greatly aroused the interest of the research team. Why is perforin selectively destroyed? Will this be the breakthrough point of the puzzle? To this end, scientists have studied perforin.
Perforin is the protein responsible for punching. They found that perforin's adhesion to cell surfaces is strongly dependent on molecules—so-called lipids in the membrane that surrounds and protects white blood cells. Initially, secreted perforin interacts with target cells through calcium-dependent membrane binding, mediated by its C2 domain. The second is oligomerization into short and non-insertion pre-hole components, and finally through the plasma membrane by inserting and further assembling the entire mature pore. Increasing orderly and tighter accumulation of lipid molecules results in reduced perforin binding, and when the order of this lipid in leukocytes is artificially disrupted, cells become more sensitive to perforin. When white blood cells are exposed to so much perforin, binding to perforin still does not kill white blood cells, suggesting that another layer of protection is necessary. Further exploration found that this is because the negative charge of some lipid molecules was transported to the cell surface and combined with the remaining perforin, preventing it from damaging the cell membrane.
In fact, existing research has suggested that local lipid sequences can change the way cells communicate. Surprisingly, precise physical membrane properties can also provide such an important protective layer against molecular punchers (perforin).
In this study, researchers learned that CTLs do this through two protective properties of the plasma membrane at the synapse: CTL membranes repel perforin by putting their lipids in an ordered state in immune synapses (lipid rafts) ) And also exposed to phosphatidylserine (PS) within the synapse, which creates a negatively charged sink, isolates and inactivates any remaining perforin. Cells' resistance to perforin supports their ability to kill multiple targets and enables them to maintain their immune balance and protect themselves. In summary, CTL protects itself from perforin by dynamically controlling its membrane lipid composition.
This study provides a theoretical basis for the optimization of cancer immunotherapy. It is expected to break the current deadlock in cancer treatment again, let us wait and see.
穿孔素是负责打孔的蛋白质。他们发现穿孔素对细胞表面的粘附强烈地依赖于 molecules—so-called 包围和保护白血球的膜中的脂质。在最初，分泌的穿孔素通过钙依赖性膜结合与靶细胞相互作用，通过其C2结构域介导。其次是低聚成短和非插入式预孔组件，并最终通过插入和进一步组装整个成熟孔跨质膜。越来越多有序和更紧密的脂质分子堆积导致穿孔素结合减少，并且当人为地破坏白细胞中这种脂质的顺序时，细胞对穿孔素便变得更加敏感。当白细胞暴露在如此多的穿孔素中，结合穿孔素仍然不能杀死白细胞，这表明必须有另一层保护。进一步探索发现，这是因为一些脂质分子的负电荷被运送到细胞表面，与剩馀的穿孔素结合，阻止它破坏细胞膜。