Study reveals new strategy to reduce tumor growth

According to a new study, tumors can escape the immune system by instructing immune cells to create immunosuppressive steroids.

Study reveals new strategy to reduce tumor growth
Image Credit: NIH, NIAID.

A team of researchers from the Wellcome Sanger Institute, Department of Pathology, University of Cambridge, and MRC Cancer Unit found that steroids are secreted by immune T cells obtained from the skin and breast tumors of mice, and that inhibiting the production of these steroids decreased tumor growth in mice.

The study also found that eliminating a major steroid-producing gene, or turning it off with a drug, significantly slowed the progression or formation of cancers.

The mouse study, which was reported in the Nature Communications journal, demonstrated that this steroid signaling route contained promising drug targets for designing new kinds of cancer immunotherapy, even though more human studies are required.

The immune system is known to be highly complex. Although immune cells guard the body against infections and tumors, certain chemicals created in the body can reduce the activity of the immune system.

This renders it relatively harder for the body to combat cancer; hence, there is an urgent need to develop cancer immunotherapies that improve the activity of the immune system.

An earlier study had demonstrated that certain immune cells, called T cells, released steroids once an infection had subsided, to bring down their activity back to low levels again. Therefore, the scientists wanted to know if tumor T cells could act in the same manner.

Using single-cell RNA sequencing, the researchers tested T cells extracted from breast tumors and melanoma in mice to closely observe which kinds of genes were turned on in every individual cell. They observed that T cells extracted from tumors indeed produce steroids, which could possibly decrease their effectiveness at fighting the tumor.

For the first time, we could see that mouse tumor 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 tumors to evade the immune system and continue growing.”

Dr Bidesh Mahata, Study Lead Author, University of Cambridge and Wellcome Sanger Institute

Dr. Mahata continued, “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 new hope in cancer, particularly for those tumors that use this trick to suppress anti-tumor immunity.”

To verify how the production of steroids is switched off, the scientists performed experiments with mice that lacked a major steroid-synthesis gene—called Cyp11a1—in their T cells. The team noted that while tumors developed quickly in normal and wild-type mice, tumor growth was suppressed in these knockout mice with any tumors being relatively slower and smaller to grow.

The researchers also demonstrated that a medication that inactivates aminoglutethimide—the Cyp11a1 protein—also decreased the tumors in healthy mice.

Using mouse models, we showed that preventing T cells from producing steroids made a huge difference to tumor growth, reducing it dramatically. We found that either removing the key gene, or preventing it from functioning with drugs, stimulated anti-tumor immunity.”

Dr Jacqui Shields, MRC Cancer Unit, University of Cambridge

Dr. Shields continued, “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.”

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 tumor defense 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.”

Dr Sarah Teichmann, Study Senior Author, University of Cambridge and Wellcome Sanger Institute

Source:
Journal reference:

Mahata, B., et al. (2020) Tumors induce de novo steroid biosynthesis in T cells to evade immunity. Nature Communications. doi.org/10.1038/s41467-020-17339-6.

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