In a new study from UT Southwestern Medical Center, experts have found that cancer cells avoid death after radiation by hijacking a cell signaling pathway to silence the anti-tumor immune response. The research may ultimately lead to methods to manipulate cell death signaling and improve cancer treatments.
Radiation kills cancer cells in two different ways. First, the high-energy beams attack some cells directly. When the dead tumor cells break apart, DNA fragments are leaked that trigger a tumor-fighting immune response through proteins known as interferons (IFNs).
However, even though cancerous cells make up the vast majority of a tumor, studies have shown that these cells secrete very little IFN themselves, explained study leader Dr. Yang-Xin Fu. This stifles the immune response that could eradicate the cancer cells. “We figured that tumor cells must have some mechanism to escape interferon production,” said Dr. Fu.
To investigate, the team studied mouse colon cancer cells growing in petri dishes. The researchers tested 42 FDA-approved drugs that block various parts of cell signaling, searching for a treatment that may prompt these cells to secrete more interferons after radiation.
The experts pinpointed a drug known as emricasan, which helps prevent rejection during liver transplants. Emricasan slows the production of enzymes known as caspases, which help trigger cell death and mute the immune system’s response to dying cells.
Upon further analysis, the researchers found that one such enzyme, caspase-9 (CASP9), played a key role in preventing the cancer cells from secreting IFN.
The researchers genetically modified cancer cells to turn off CASP9 production. They found that radiation dramatically increased IFN production compared with cancer cells that had not been manipulated.
In mice, the CASP9-deficient cancer cells allowed the tumors to completely regress after radiation. Additional experiments revealed the tumor regression was facilitated by a specific population of immune cells, known as CD8+ T cells, which were recruited by the secreted interferon.
Even though blocking CASP9 production appears to be a promising way to boost the anti-tumor immune response, the researchers discovered a drawback. When the tumors in animal models lost CASP9 signaling, the cells found a new way to evade immune attack by elevating the production of a protein called programmed death-ligand 1 (PD-L1). This protein shields cancer cells from immune discovery.
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, said Dr. Fu.
“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 be able to give some patients long-lasting survival that’s not yet achievable.”
The study is published in the journal Nature Immunology.
By Chrissy Sexton, Earth.com Staff Writer