It may be possible to use drugs that are already in development to overcome radiotherapy resistance in tumors, which is often a major barrier to the successful treatment of many cancers.
This was the conclusion of a recently published Nature Communications study, in which researchers uncovered an immune system mechanism that helps tumors to develop resistance to radiation therapy.
The study builds on earlier work, in which the team examined what happens to cancer cells when they are exposed to radiotherapy, and in particular, how the immune system responds.
For many patients, the aim of cancer treatment is to cure the disease, but, in some cases, this may not be feasible and so the goal is to manage symptoms and control the disease.
Most treatments involve surgery combined with one or more therapies, including chemotherapy and radiation therapy, and perhaps even hormonal or biological therapy.
Radiation therapy shrinks tumors by directing X-rays, gamma rays, or charged particles at them. These high-energy beams — which can come from a machine outside the body or from radioactive materials implanted into the body — kill the cancer cells by destroying their DNA.
There is also a type of radiation therapy, called systemic radiotherapy, in which the radioactive material travels to the cancer cells in the bloodstream.
In their study paper, the researchers note that around 50–60 percent of cancer patients receive some form of radiotherapy as part of their treatment.
Unfortunately, around 40 percent of large tumors that are treated with radiotherapy eventually become resistant, causing significant problems. Finding ways to defeat the resistance would do much to help patients, many of whom suffer a lot of discomfort, as their tumors cannot be removed and fail to respond to other types of treatment.
“It has been known for some time that radiation induces inflammation,” says Dr. Ralph Weichselbaum, of the Ludwig Center for cancer research at the University of Chicago, IL, and co-leader of the study, “and we’ve shown in our earlier work that it does so through a molecular sensor found in cells known as the stimulator of interferon genes, or STING.”
He goes on to explain that, as well as the “good side” of the radiotherapy — in which the immune system attacks the damaged cancer cells — there is also a “dark side” that suppresses the immune response.
This dual mechanism surrounds the action of STING. On the one side, STING helps to find the irradiated cancer cells by detecting the DNA fragments produced by the radiation. This triggers the immune system to produce type 1 interferons that promote killer T cells that find and destroy sick cancer cells. The attack by killer T cells is what causes tumors to shrink.
But the team found that the same mechanism also appears to play a role in developing tumor resistance to radiotherapy.
They found that the longer-term effect of the STING/type 1 interferon signaling is to cause an influx of monocytic myeloid-derived suppressor cells (M-MDSCs), which suppress the immune response.
In mouse models of colon and lung cancer, the researchers found that STING activates a protein on cell surfaces of M-MDSCs called CCR2.
They confirmed the role of CCR2 by testing mice bred to lack CCR2 – their tumors were much less resistant to radiotherapy.
In another set of tests, the team found that using an antibody to block CCR2 also reduced radiotherapy resistance in the tumors of mice that could make CCR2. This showed that it might be possible to block CCR2 with drugs.
Finally, the researchers found that the tumors shrank even more when radiation therapy was accompanied by two types of drug – one that activates STING and an anti-CCR2 antibody. The first stimulates the immune system and the second stops it being suppressed.
“Our current study is of immediate relevance to radiation therapy, but we think it may also have significant implications for chemotherapy and immunotherapy as well.”
Dr. Ralph Weichselbaum
Drug companies are already developing cancer drugs that activate STING. One is already undergoing clinical trials as an accompaniment to a type of immunotherapy that promotes a particular type of T cell attack.
In addition, there are some CCR2 antibodies also in development for use in immunotherapy treatment.
The researchers suggest that their study has paved the way for exploring how to combine the two drugs to boost the effectiveness of radiotherapy on several types of solid tumor.
“What we’ve shown in this preclinical study,” Dr. Weichselbaum concludes, “is that if you block the influx of these MDSCs, you can, to a large extent, pre-empt resistance to radiation therapy.”