US, WASHINGTON (ORDO NEWS) — Tumor cells are able to avoid an attack from the immune system after irradiation, using the same signaling pathways by which dying cells avoid triggering an immune response. An article about this was published in Nature Immunology.
Radiation therapy is the basis of most treatment protocols for a wide variety of cancers. High-energy radiation kills tumor cells from the nuclei of which DNA is released: it, in turn, becomes a trigger for an interferon-mediated immune response. Although mutated cancer cells make up most of the tumors, they themselves secrete very little interferon.
This led scientists to the idea that there is a certain mechanism that allows the tumor to avoid the immune response.
Researchers at the Northwest Texas Medical Center have tried to identify this mechanism. They tested 42 FDA-approved drugs that block various signaling pathways in mouse intestinal cancer cell culture. Scientists were trying to find among these drugs that which could induce cells to synthesize large amounts of interferon.
Emricasan, developed for the treatment of chronic liver failure, turned out to be such a drug. By its mechanism of action, emricasan is an inhibitor of caspases, enzymes that play an important role in programmed cell death processes and, at the same time, inhibit the response of the immune system to dying cells.
Further experiments showed that one enzyme from this family, caspase 9, serves as a key substance for suppressing the synthesis of interferons. Genetic manipulations aimed at shutting down the CASP9 gene encoding this caspase led to the fact that after radiation exposure, the synthesis of interferons by tumor cells increased by a factor of 1,000 compared with wild-type cells (with the working CASP9 gene).
When the researchers transplanted cancer cells with the CASP9 genes turned off to mice, their tumors almost completely regressed after the irradiation session. Additional experiments showed that a specific population of immune cells, the so-called CD8 + T-lymphocytes, was involved in the process of eliminating tumor cells. They were recruited to fight cancer cells through interferon.
However, the question of how exactly the protective mechanism of cancer cells works remains open. The fact is that nuclear DNA is released after the death of the cell: therefore, there is a certain molecular trigger that stimulates the activation of caspases when the cell has not yet died. This trigger turned out to be mitochondrial DNA, which is released into the cell cytoplasm before nuclear. When the authors of the study removed all mitochondrial DNA from tumor cells, this led to the absence of interferon synthesis in response to irradiation.
Although blocking the gene for the synthesis of caspases seems like a promising way to fight cancer, this method has a significant drawback. With the loss of caspase 9 synthesis, tumor cells have developed a new method of avoiding the immune response – through the programmed cell death protein PD (L) 1.
Therefore, the simultaneous administration of emricasan and antibodies against PD (L) 1 can be an effective way to suppress cancer cells. “This approach can ultimately give doctors confidence that they irradiate a tumor that they can see and use the immune system to destroy tumor cells that they have not observed,” adds lead author of the study, Yang-Xin Fu. According to the scientist, this can also increase the effectiveness of therapy and patient survival.
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