Study Finds Cancer Cells Avoid Immune System After Radiation Through Cell Signaling Pathway

Cancer cells avoid an immune system attack after radiation by taking control of a cell signaling pathway that helps dying cells avoid triggering an immune response, according to a study published in Nature Immunology.

Researchers have long known that radiation, a mainstay of treatment protocols for many types of cancerous tumors, kills cancers in 2 ways: the high-energy beams kill certain cells directly, and these dead cells leak DNA that triggers a tumor-fighting immune response through proteins known as interferons (IFNs). Although cancerous cells comprise the vast majority of a tumor, studies have shown that these cells secrete very little IFN themselves, muting the immune response that could eradicate them.

In order to determine what the mechanism may be to escape IFN production, a research team at UT Southwestern Medical Center tested 42 FDA-approved drugs that block various parts of cell signaling on model colon cancer cells growing in petri dishes, searching for any that might be able to prompt these cells to secrete abundant IFNs after radiation

Their search identified a drug called emriciasan, which is often prescribed to patients who have received a liver transplant. This drug broadly inhibits production of a family of enzymes known as capases, which not only help trigger cell death but also muffle the immune system’s response to dying cells.

Further experiments indicated that a particular member of this family, known as caspase-9 (CASP9), was key for preventing the cancer cells from secreting IFN. When the researchers genetically manipulated cancer cells to turn off CASP9 production, radiation increased their IFN production thousands-fold compared with wild-type cancer cells that hadn't been modified.

When the researchers placed these CASP9-deficient cancer cells into tumor models, they completely regressed after radiation compared with those carrying tumors made of wild-type cells. Additional experiments showed that a particular population of immune cells, known as CD8+ T cells, were recruited by the secreted interferon and were responsible for this dramatic regression.

Peering deeper into the mechanism behind how CASP9 helps protect tumor cells from the immune system, the researchers looked from the molecular trigger behind the production of this enzyme. Because cells secrete DNA from the nucleus only after they’re dead, the researchers looked to an event that occurs earlier after radiation damage: the secretion of DNA from mitochondria, the cell’s power-generating organelles. When the researchers removed mitochondrial DNA from cancer cells, they no longer produced IFN when they were irradiated, suggesting that this was a triggering event, according to the study.

Although blocking CASP9 production appears to be a promising way to boost the anti-tumor immune response, it comes with a significant drawback, according to the researchers. When tumors in animal models lost CASP9 signaling, these masses found a new way to evade immune attack by stepping up production of the protein programmed death-ligand 1 (PD-L1), which shields cancer cells from immune discovery.

However, when the researchers administered an antibody that blocked PD-L1, the tumors regressed again. Using a combination of CASP9 inhibitors with anti-PD-L1 could offer a new strategy for boosting the effects of radiation

According to the study authors, this approach could eventually give doctors the confidence that they’re irradiating the tumor that they can see and using the immune system to knock out other tumor cells that they can’t see. Together, this may give some patients long-lasting survival that’s not yet achievable, according to the study.

Reference

• Tumors hijack the cell death pathway to live. UT Southwestern Medical Center website. Published April 13, 2020. https://www.utsouthwestern.edu/newsroom/articles/year-2020/tumors-hijack-the-cell-death-pathway-to-live.html. Accessed April 16, 2020.