Canceling the "don't eat me" signal

"Smart molecules" turn macrophages into cancer cell destroyers

Anna Kerman, XX2 century, based on Medical Xpress: Smart molecules trigger white blood cells to become better cancer-eating machines

A team of researchers has created "smart" protein molecules that make white blood cells ignore the signals of the self-defense mechanism of cancer cells. The researchers say this breakthrough could lead to a new method of rebuilding immune cells. After "reprogramming" they will learn how to fight cancer and infectious diseases. The team successfully tested the new technique on the culture of living cells.

The work was led by bioengineering professors Peter Yingxiao Wang and Shu Chien in collaboration with Professors Victor Nizet and Xiangdong Xu from the University of California, San Diego and other researchers. The results of the work are published this month in Nature Communications (Sun et al., Engineered proteins with sensing and activating modules for automated reprogramming of cellular functions).

"Smart squirrels", they are also iSNAPS (Eng. integrated sensing and activating proteins — integrated recognizing and activating proteins) are designed to recognize certain molecular signals in living cells and respond to them, prompting cells to fight disease or perform other actions. As Wang said, this study showed for the first time how both functions — recognition and activation — can be combined in a single molecule.

The researchers injected iSNAPS into a macrophage (a white blood cell). This significantly improved the macrophage's ability to absorb and destroy rapidly dividing cancer cells.

Macrophages are white blood cells that play an important role in the immune system. One of their tasks is to remove dangerous particles and harmful organisms from the body, such as pathogens and tumor cells. Macrophages do this by absorbing enemies. When a macrophage binds to a cancer cell or pathogen, a protein on the surface of the macrophage (Fc-gamma receptor) sends a "eat me" signal, forcing the "devourer" to absorb and destroy the enemy.

But cancer cells have a special defense mechanism, which is why they become so dangerous. On their surface is the CD47 protein, which interacts with the SIRP alpha protein and forces it to send a "don't eat me" signal.

In order for the iSNAPS method to work, it is necessary to change the process of interaction between cancer cells and the immune system. iSNAPS, in fact, "reprograms" macrophages so that they interpret the command "don't eat" as an order to absorb. iSnap has a sensory component that detects a key molecular event occurring inside a macrophage when its surface protein SIRP alpha interacts with CD47 on a cancer cell. iSNAPS also contains an activating component that changes immediately, sending a "green/yellow light" signal, which gives scientists the opportunity to see the molecular activity through a microscope. In addition, the activating component releases an enzyme that triggers a chain of events that allow the macrophage to absorb the cancer cell. "Separately, it is worth noting that the response is very fast — we believe it takes several seconds to several minutes," Wang said.

During the experiments, the researchers connected the altered macrophages with cancer cells in Petri dishes, and then monitored through a microscope. Macrophages were able to absorb most of the cancer cells. As a control sample, the scientists used macrophages with iSNAPS, where the sensory function was turned on and the activating function was blocked. Such macrophages bound to cancer cells, but could not "eat" them.

In the video, large blue cells are macrophages, green and yellow dots are tumor cells. Above: macrophages reprogrammed with iSNAPS quickly absorb and destroy cancer cells.
Bottom: cancer cells get stuck on the surface of control macrophages – VM.

Wang noted that the iSNAPS method can be adapted for other actions, for example, it can be used to reprogram immune cells to kill bacteria, or apply it to T cells as part of multi-stage cancer therapy. Next, the team of scientists plans to conduct experiments with iSNAPS on mice to test how the modified proteins behave in the body. Researchers are also interested in whether it is possible to strengthen other natural functions of cells with the help of iSNAPS in order to combat various pathologies.

Portal "Eternal youth" http://vechnayamolodost.ru  03.10.2017