Unraveled: How tumours grow resistant to radiotherapy

tumoursScientists have unraveled a mechanism by which tumours develop resistance to radiation therapy and have also shown how such resistance might be overcome with drugs that are currently under development.

“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,” says Ralph Weichselbaum, Co-director of the Ludwig Centre at Chicago, who led the study.

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.

Using mouse models of lung and colon tumours, the researchers found that the tumour-infiltrating monocytic myeloid-derived suppressor cells (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.

More significantly, in both types of mice the destruction of tumours 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,” says Weichselbaum.

“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,” he added.

The study was published in the current issue of Nature Communications.

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