How Cancer Cheats T-Killers
To survive, cancer cells force T-killers to "bite" rather than kill
The first attempts to recruit the immune system to fight cancer are attributed to the beginning of the last century, and today "cancer immunotherapy" is actively used in practical medicine, although its effectiveness still leaves much to be desired. Recently, scientists have uncovered another mechanism by which tumor cells can bypass both the natural immune response and therapeutic strategies.
The human immune system protects it from both external threats, such as pathogenic microbes, and "internal" ones, destroying damaged and regenerated own cells of the body. Mutations that can lead to malignant degeneration occur constantly, and cells of the immune system (T- and B-lymphocytes, macrophages, dendritic cells) usually successfully cope with them.
But sometimes anti-cancer mechanisms fail, in which the tumor cells themselves play an important role, which are actively "hiding" from the immune system. In particular, these cells secrete a variety of molecules that prevent their destruction by cytotoxic T-lymphocytes, which are not without reason called T-killers.
The study of these mechanisms made it possible to develop a set of therapeutic strategies known as cancer immunotherapy. The most well–known method is CAR T therapy, in which the patient's own T cells are modified "in vitro", specifically targeting them to the cells of a specific human tumor, and then injected back into the body. However, there are many pitfalls in this method of treatment, since the mechanisms of interaction between the immune system and the tumor are only partially elucidated.
Recently, a group of scientists led by specialists from the University of Pennsylvania (USA) we investigated how the tumor stimulates T-cell trogocytosis (from Greek. trogo – "gnaw" or "chew").
Normally, the process of destroying cancer cells begins with the fact that T-killers recognize specific antigen molecules located on the surface of such cells. But sometimes it happens that the T-cell only "bites off" a part of the cell membrane with a tumor antigen and begins to present it on its surface itself.
For reasons that are not fully understood, such a T-cell becomes less active. Moreover, it becomes a "sheep in wolf's clothing", and other T-cells can identify it as cancerous and destroy it. At the same time, the cancer cell itself not only does not die, but turns into "invisible" to other T cells.
How does a cancer cell "make" a T-cell trogocyte? As it turned out, the substances secreted by the tumor cause an increase in the production of the protein transcription factor ATF3 in immune cells, which suppresses the production of an enzyme involved in the synthesis of 25-hydroxycholesterol. And a decrease in the reserves of these molecules in the cell leads to disturbances in the process of cell membrane fusion, which increases the likelihood of trogocytosis events.
Scientists proved this conclusion in an experiment where 25-hydroxycholesterol was added to trogocytizing T cells - the process of "biting off" the membranes stopped. And the complete removal of ATF3 molecules from the environment prevented trogocytosis itself and restored the ability of T-killers to kill tumor cells.
The obtained results opened up the possibility to improve the effectiveness of immunotherapy using CAR-T cells. Indeed, when researchers modified T cells by adding a gene encoding cholesterol-25-hydroxylase to their genome, such cells coped better with the tumor in mice serving as an animal model of cancer.
So although trogocytosis is characteristic of only a small part of T cells, this process is clearly underestimated when it comes to anti-cancer immunity, when every identified and destroyed malignant cell is important. In the future, this mechanism should be studied in detail, which may allow not only to improve the effectiveness of CAR-T therapy, but also to develop new immunotherapy strategies.
The article by Lu et al. ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes is published in the journal Cell Metabolism.
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