▎ WuXi AppTec content team editor
The human body is made up of trillions of cells, but regardless of the morphology of the cells and the function they perform, they all share a common feature, a protective membrane structure formed by bilayered phospholipids, which is also called the cytoplasmic membrane.
Plasma membranes protect cells from environmental influences and act as gatekeepers for the exchange of substances inside and outside the cell. When the plasma membrane is under too much pressure, whether it is hypoxia, lack of nutrients or drug effects, the plasma membrane will cause damage and lead to cell death.
Cancer cells also depend on intact and fully functional plasma membranes to survive, and immune cells, which are the main force of cancer control, are well aware of this. For example, cytotoxic T lymphocytes (CTLs) have a unique means of treating the plasma membrane of cancer cells: secreting two proteins to destroy the plasma membrane and promote cancer cell death.
▲The new research appeared on the cover of the latest issue of Science
The perforin and granulase secreted by CTL are toxin proteins that can cooperate to produce cytotoxicity. Perforin is able to form holes in the plasma membrane, and granulase can act as a proteolytic enzyme, entering the cancer cell from the hole to induce programmed death in the cell.
However, evading cell death is one of the hallmarks specific to cancer cells. Although the CTL strategy is complete, cancer cells still develop in some people. Science's new research has found that cancer cells do not surrender to CTL, they can fight back against CTL behavior.
Using high-resolution imaging and live cell functional analysis, a team of researchers from Genetech, a U.S.-based genetic engineering company, found that the endogenous protein sorting transporter (ESCRT) produced by cancer cells can be used to defend against the attack of the two proteins of CTL. It repairs holes created by perforatins in the plasma membrane to delay the entry of granulase into the cell, or even prevent them from entering altogether.
According to their observations, after the release of perforin, a large amount of ESCRT was precisely recruited to the binding site of CTL. This shows that cancer cells are very purposefully defending against CTL.
A real-time image of CTL attacking cancer cells, rosy color representing that they are secreting toxic proteins (Image source: Reference[1], credit: Alex Ritter)
ESCRT actually plays a role in normal cells, but is usually involved in regulating the process of cell death. Since the plasma membrane may experience various stress damage at any time, ESCRT acts as a protective and repairing plasma membrane.
They can inhibit apoptosis caused by plasma membrane damage in time and save normal cells. If ESCRT-related signaling pathways are persistently suppressed, cells will also die.
When CTL invades cancer cells, a large number of ESCRTs are recruited to the junction (yellow arrow) (Image source: Reference[3])
It's just that in cancer cells, this natural rescue strategy has become a magic weapon for them to save their lives. The researchers used CRISPR technology to knock out the Chmp4b gene of the ESCRT pathway in cancer cells, so that some of the functions of ESCRT would be lost, and these cancer cells could be more easily killed by CTL, and their sensitivity to CTL attacks increased significantly.
Peter Friedl, a professor of medicine at radberg University in the Netherlands, was not involved in the study, but he noted that the new study's innovative use of imaging techniques and molecular interventions reveals a key mechanism for perforatin and plasma membrane repair.
"ESCRT could be a potential target for immunotherapy improvement, and according to their study, just adjusting the function of ESCRT has increased the tumor killing efficiency of immune cells by 2-3 times," Professor Friedl said, "interfering with the function of ESCRT is likely to become a new type of targeted therapy that enhances the ability of CTL to cause damage." ”
Resources:
[1] Preventing Attacked Cancer Cells from Repairing Membranes May Enhance Immunotherapy. Retrieved Apr 24th, 2022 from https://www.genengnews.com/topics/cancer/preventing-attacked-cancer-cells-from-repairing-membranes-may-enhance-immunotherapy/
[2] Plasma membrane repair protects tumor cells against killer T cell assault. Retrieved Apr 24th, 2022 from https://www.eurekalert.org/news-releases/949943
[3] ESCRT-mediated membrane repair protects tumor-derived cells against T cell attack. Science (2022), DOI: 10.1126/science.abl3855
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