How to overcome the ineffectiveness of melanoma immunotherapy
Cancer immunotherapy and cellular signaling pathways
However, such therapy has little effect on some patients. To understand why this happens, the University of Chicago (USA) studied the molecular features of tumors of such patients. The results of the study were published in the journal Nature (Spranger et al., Melanoma-intrinsic beta-catenin signaling prevents anti-tumour immunity – VM).
As a result of DNA copying errors or adverse environmental effects, mutations may appear in the cells of the human body. In most cases, such DNA damage is corrected by the cell itself. If this does not happen, then the immune system becomes the second line of defense: its cells, T-lymphocytes and natural killers, are able to recognize the damaged cell and destroy it.
Immune system cells attack cancer cells. A drawing from Wikimedia is given in the UChicago press release
Disrupting cancer pathway could enhance new immunotherapies – VM.
A necessary condition for the development of a cancerous tumor is the emergence of mechanisms for avoiding the attacks of the immune system. One of these mechanisms is the effect of the tumor on special T-lymphocyte receptors, which leads to their inactivation or even death. New methods of melanoma immunotherapy are aimed at blocking certain T-lymphocyte receptors with the help of drugs and thereby preventing the inactivation of these cells. As a result, the tumor is attacked by the immune system. Sometimes the effectiveness of such therapy is so high that it creates a new threat to the patient's health: the tumor disappears within a short time, leaving an empty space in its place. However, some patients do not respond to this therapy.
A study conducted at the University of Chicago showed that in such patients there is no infiltration (penetration) of T-lymphocytes into the tumor. In addition, the cancer cells of such patients produce a larger amount of a protein called beta-catenin.
In order to understand the relationship between elevated beta-catenin levels and infiltration of T-lymphocytes, experiments were conducted on mice. It turned out that beta-catenin in tumor cells suppresses the synthesis of another protein – CCL4. In the absence of beta-catenin, the CCL4 protein is produced in significant quantities and released by cells to the outside. Once in the intercellular space, CCL4 attracts another type of immune system cells called dendritic cells. They are involved in the immune response and regulate the infiltration of T-lymphocytes into the tumor.
To confirm the observations made, tumors were artificially induced in mice. Some of them had an increased amount of beta-catenin, there was no infiltration of T-lymphocytes, and they did not respond to immunotherapy. However, after injection of dendritic cells directly into the tumor, T-lymphocytes began to actively penetrate there, and the use of immunotherapeutic drugs gave results.
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