Radiation therapy induces good inflammation and bad inflammation. The good inflammation boosts the activation of killer T cells and helps shrink tumors. The bad inflammation causes an influx of suppressive immune cells and gives rise to radiation resistance. These opposed tendencies, which may tip radiotherapy outcomes one way or another, are even more finely balanced than one might suppose. Both are influenced by the same signaling mechanism: the stimulator of interferon genes, or STING.

The good inflammation associated with STING has been understood for several years, ever since scientists at the Ludwig Institute for Cancer Research showed that STING, a sensor of DNA fragments, links the detection of such fragments to the production of immune factors known as type I interferons. These factors ultimately boost the activation of killer T cells—immune cells that attack sick and cancerous cells—and cause much of the destruction of tumors associated with radiation therapy.

Following up on this work, the Ludwig researchers tested their hunch that the STING/type I interferon signaling cascade might also account for the resistance that tumors develop to extended radiotherapy. Ultimately, the researchers not only confirmed their suspicions, they also learned that resistance to radiation therapy might be overcome with drugs that are currently under development.

Details of the researchers’ work appeared November 23 in the journal Nature Communications, in an article entitled “Host STING-Dependent MDSC Mobilization Drives Extrinsic Radiation Resistance.” The article presents findings that could help explain why as many as 40% of large tumors develop resistance to radiotherapy. In addition, the article identifies a drug target that could be exploited in combination therapies, improving the radiotherapy effectiveness.

“The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 [C-C chemokine receptor type 2] pathway,” wrote the article’s authors. “Germ-line knockouts of CCR2 or treatment with an anti-CCR2 antibody results in blockade of radiation-induced MDSC infiltration.” MDSC infiltration refers to the influx of monocytic myeloid-derived suppressor cells (M-MDSCs) that are drawn into a tumor due to long-term STING/type I interferon signaling.

“Treatment with anti-CCR2 antibody alleviates immunosuppression following activation of the STING pathway, enhancing the anti-tumor effects of STING agonists and radiotherapy,” the authors continued. They also suggested that the immunosuppressive effects of radiotherapy and STING agonists could be abrogated in humans by a translational strategy involving anti-CCR2 antibody treatment to improve radiotherapy.

“It has been known for some time that radiation induces inflammation, 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,” said Ralph Weichselbaum, M.D., co-director of the Ludwig Center at Chicago, who led the study with Yang-Xin Fu, M.D., Ph.D., of the UT Southwestern Medical Center. “However, there's a dark side to radiation: after it causes good inflammation—which mounts an immune attack on cancer cells in the irradiated tumor—it causes a bad kind of inflammation that suppresses immune responses.”

In the current study, the researchers used mouse models of lung and colon tumors to demonstrate that the tumor-infiltrating M-MDSCs express a cell-surface receptor known as CCR2, whose ligand—or binding target—is expressed by cells upon STING activation. They then showed that resistance to radiotherapy was significantly reduced in mice engineered to lack CCR2.

To determine whether the effect might be translated into clinical practice, the researchers checked whether it could be reproduced in mice that express CCR2 with the use of antibodies to the receptor. They found it could. Most notably, in both types of mice, the destruction of tumors was significantly boosted when the radiation therapy was delivered along with a STING-activating drug and anti-CCR2 antibodies.

“What we did by combining those treatments was to stimulate the immune system while alleviating immune suppression, and that worked best to improve responses to radiotherapy—more than either did alone,” explained Dr. Weichselbaum.

Pharmaceutical companies are developing STING-activating drugs for cancer therapy, and one is currently being evaluated in clinical trials in combination with checkpoint blockade—a type of immunotherapy that boosts T-cell attack on certain types of tumors. Similarly, antibodies to CCR2 are also being developed as potential immunotherapeutic agents. The current study lays the groundwork for combining these experimental drugs to improve the effects of radiotherapy for a variety of solid tumors.

“What we've shown in this preclinical study is that if you block the influx of these MDSCs, you can, to a large extent, preempt resistance to radiation therapy,” asserted Weichselbaum. “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.”

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