Six years ago, researchers noticed that in the wake of a cleared infection, T cells produced a steroid to slow from “full ahead” to “standby.” At the time, the T cells themselves were observed to be in control of their engine order telegraph. It was suspected, however, that cancer, too, might reposition the telegraph’s handle. That suspicion has just been confirmed.
A new study from researchers representing the Wellcome Sanger Institute, the University of Cambridge, and MRC Cancer Unit demonstrates that tumors somehow signal T cells to produce immunosuppressive steroids, effectively taking control of the immune system’s anticancer flagship. By inducing T cells to cut their engines, tumors can escape the immune system.
The finding recently appeared in Nature Communications, in an article titled, “Tumors induce de novo steroid biosynthesis in T cells to evade immunity.” The article also indicated that T cells can maintain full speed while fighting a tumor—if steroidogenesis in the T cells is inhibited.
“Using a transgenic steroidogenesis-reporter mouse line,” the article’s authors wrote, “we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate antitumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore antitumor immunity.”
Essentially, the scientists discovered that immune T cells from mouse skin and breast tumors secrete steroids, and that preventing this steroid production reduced growth of tumors in mice. After using single cell RNA sequencing to see exactly which genes were switched on in each individual cell, the scientists determined that either removing a key steroid-producing gene, or switching it off with a drug, dramatically slowed the formation or progression of cancers.
The scientists concluded that the T cell steroidogenesis pathway could be targeted by drugs to prevent antitumor immunosuppression.
“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,” noted Bidesh Mahata, PhD, one of the study’s three corresponding authors and a researcher affiliated with both the University of Cambridge and the Wellcome Sanger Institute. “It appears that tumors could be instructing their T cells to produce steroids, which would then allow the tumors 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 tumors that use this trick to suppress antitumor immunity.”
To test switching off the steroid production, the researchers worked with mice that were missing a key steroid-synthesis gene—Cyp11a1—from their T cells. The researchers discovered that whereas tumors developed rapidly in normal, wild-type mice, tumor growth was inhibited in these knockout mice with any tumors being much smaller and slower to grow. They also showed that a drug that inactivates the Cyp11a1 protein, aminoglutethimide, also reduced the tumors in normal mice.
“Using mouse models, we showed that preventing T cells from producing steroids made a huge difference to tumor growth, reducing it dramatically,” said Jacqueline D. Shields, PhD, another corresponding author and a researcher at the MRC Cancer Unit Cambridge. “We found that either removing the key gene, or preventing it from functioning with drugs, stimulated antitumor 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.”
“This study,” declared Sarah A. Teichmann, PhD, a senior and corresponding author from the Wellcome Sanger Institute, “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.”