Solve the "Cell Murder Case" and Now Have Hope in Treating Cancer

　　【Today’s Viewpoint】

　　◎Our reporter Zhang Mengran

　　Scientists have spent nearly 25 years solving a "cell murder case." By the way, another "T cell disappearance case" was also solved.

　　A growing body of evidence, from fruit flies to mice to humans, suggests that cannibalistic cells may contribute to rare human immune deficiencies. Now, the discovery may offer new hope for treating cancer.

　　Dennis Montel, a professor of molecular, cellular and developmental biology at the University of California, Santa Barbara, said the new research takes people from very basic cell biology to explaining the principles of human disease and using this knowledge to develop cancer treatments. Each step in between is a major discovery, and they appear together in a paper published in the Proceedings of the National Academy of Sciences.

6-8 "criminals" kill 900 members

　　The protagonist of the "case" is the Rac2 gene and the protein it encodes.

　　Rac2 is one of the three human Rac genes. The Rac family is very ancient in evolution. It can be said that it is an almost universal regulator of cell movement. But as early as the 1990s, Montel noticed that an overactive form of the Rac protein, expressed in just a few cells of the Drosophila egg chamber, destroyed the entire tissue: expressed in 6 to 8 cells This active Rac kills the entire tissue, which is composed of about 900 cells.

　　Why is this happening? Why is it so lethal?

　　There is growing evidence that cell eating, also known as cannibalism, is associated with tissue destruction. There is a step in normal fruit fly egg development in which certain cells eat their neighbors. This cannibalism is not unusual: millions of old red blood cells disappear from the body in this way every second.

　　Rac2 is part of this cannibalism process, because Rac helps the feeding cell wrap around its target.

　　But when Montel's team saw the solution of this "old case" that had continued to trouble people for 25 years, they were still puzzled: Does it only occur in the niche field of fruit fly development? Will this result expand?

Vital T cells disappear

　　At the time of the breakthrough in the "old case," Montel came across an interesting study in the journal Blood. The paper found that three completely unrelated patients with recurrent infections had exactly the same mutation that overactivated the Rac2 protein produced in blood cells. Montel realized that his lab's latest findings in fruit flies might shed light on this mystery.

　　The patients' mutations were only mildly activating, but enough so that they all suffered from multiple infections and eventually required bone marrow transplants. Blood tests showed that these patients had almost no T cells, a special type of white blood cell that is vital to the immune system.

　　At the same time, a team from the National Institutes of Health inserted the Rac2 mutation into mice and discovered that the same mysterious "T cell disappearance case" occurred. T cells with overactive Rac developed normally in the animals' bone marrow and migrated to the thymus, where they continued to mature without incident. But then they suddenly disappeared. This brings up a new mystery: What causes T cells to disappear?

　　Montel's team found that the patients' innate immune cells, such as neutrophils with active Rac2, were eating the T cells, much like Drosophila cells with active Rac eat the egg chamber. They turned their attention to macrophages, which are more "voracious" than neutrophils. Further experiments observed that macrophages with overactive Rac ate ​​more cells, confirming the team's hypothesis.

　　After repeated comparisons and studies, the team's most likely explanation for the "T cell disappearance case" in human patients is that the increase in macrophage "eating" is related to the increased vulnerability of the T cells themselves.

　　This time, they solved a human medical mystery.

"Kill cancer cells if you can."

　　These effects finally expanded in January 2020. Study co-author Megan Morrisey programmed macrophages into CAR-M, a new way to treat cancer cells. Because Morrissey discovered that macrophages can be induced to eat more, and their ability to do so consumes and kills entire cancer cells.

　　In other words, this provides clinicians with a way: since macrophages have this ability, modified macrophages can be used to focus on attacking cancer cells. People also don't need to worry that the engineered cells will eat up the patient's important T cells, because the T cells won't have active Rac2 mutations.

　　The currently popular CAR-T cancer therapy uses CAR receptors and the patient's own T cells to attack and destroy cancer. It is effective against cancers such as leukemia and lymphoma, but has little effect against breast, lung and colon cancers. CAR-M can be regarded as the "new cousin" of CAR-T. It has recently entered human clinical trials and is safe so far.

　　The researchers have applied for a provisional patent for the technology, RaceCAR-M, and have invited biotech companies to collaborate on further development. The team also needs to explore how many types of cancer RaceCAR-M therapy can successfully target.

　　This remarkable research helps scientists solve a long-standing mystery of human immune deficiency. What's interesting is that "one mystery after another, and Rac turned out to be the answer to each mystery." Ultimately, scientists succeeded in using the new knowledge to enhance humanity's armamentarium against cancer. (Science and Technology Daily)