Cancer immunotherapy boost as Sanger Institute and University of Cambridge reveal role of immune cell steroids
Potential new targets for cancer immunotherapy have been uncovered in a study exploring the role of steroids and the immune system.
Researchers at the Wellcome Sanger Institute in Hinxton, the Department of Pathology at the University of Cambridge and the MRC Cancer Unit discovered that immune T cells from mouse skin and breast tumours secrete steroids.
Preventing the steroid production – by removing a key steroid-producing gene, or switching it off with a drug – dramatically slowed the formation or progression of tumours in mice.
Although human studies are required, the steroid signalling pathway in mice suggests potential drug targets for new types of cancer immunotherapy .
While our immune systems protect us from tumours and infections, some chemicals we produce can dampen down its effects, making it harder to ward off cancer.
Cancer immunotherapies aim to restore the system’s activity.
Following work by the Sanger Institute and the European Bioinformatics Institute (EMBL-EBI) that showed immune cells known as T cells produced steroids after an infection had passed to reduce their activity back to low levels again, the researchers in the latest study aimed to see if tumour T cells could behave in the same way.
They used single cell RNA sequencing on T cells from melanoma and breast tumours in mice to find out which genes were switched on in each cell.
They found that T cells from tumours do produce steroids, which may reduce their effectiveness in battling the cancer.
Dr Bidesh Mahata, the lead author from the University of Cambridge and the Wellcome Sanger Institute , said: “For the first time, we could see that mouse tumour T cells were producing immunosuppressive steroids, even though T cells from healthy mice didn’t.
“It appears that tumours could be instructing their T cells to produce steroids, which would then allow the tumours to evade the immune system and continue growing.
“This is a really exciting discovery as it means there might be a way of switching the steroid production off again to treat cancer. This is a new hope in cancer, particularly for those tumours that use this trick to suppress anti-tumour immunity.”
Researchers worked with mice missing a key gene involved in steroid synthesis – Cyp11a1 – from their T cells.
In contrast to the rapid development of tumours in normal mice, the growth was inhibited in these ‘knockout mice’. Any tumours were smaller and slower to grow.
They also demonstrated that a drug that inactivates the Cyp11a1 protein called aminoglutethimide also reduced the tumours in normal mice.
Dr Jacqui Shields, from the MRC Cancer Unit Cambridge, said: “Using mouse models, we showed that preventing T cells from producing steroids made a huge difference to tumour growth, reducing it dramatically.
“We found that either removing the key gene, or preventing it from functioning with drugs, stimulated anti-tumour immunity. This suggests the steroid-production pathway could be a real contender in the search for drug targets for designing cancer immunotherapies to help treat cancer patients.”
Dr Sarah Teichmann , a senior author from the Wellcome Sanger Institute , said: “This study may pave the way for new hope in cancer immunotherapy.
“While these results are from mice, preliminary data from human tissues suggests that the same tumour defence may happen in people and we now need further research to show direct evidence in human cancer.
“If this is confirmed, in the future, it might be possible to target this immunosuppressive pathway, to create new treatments to switch the immune system back on, and help save lives.”
The study was reported in Nature Communications.
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