A new study co-led by Oncode Investigator Jarno Drost (Princess Máxima Center) has found that the soft tissue tumor rhabdomyosarcoma hijacks the healthy cells around it to hide from the immune system. The researchers also made a detailed ‘atlas’ of the different cell types in the tumor, and found that they varied in maturity. The findings point to possible immunotherapy targets for rhabdomyosarcoma. The results could also help pick out children with high or low risk forms of the disease, and develop more tailored treatment options. The study is published in Nature Communications.
Rhabdomyosarcoma is a soft tissue tumor that looks like muscle. Around 20 children in the Netherlands develop the disease each year. Some children have a good outcome from treatment with chemotherapy and surgery, but more than half of children don’t survive their disease. Four out of five children with the most aggressive form of rhabdomyosarcoma die within five years after diagnosis. Better, more tailored treatments are desperately needed.
“To move the needle for children with rhabdomyosarcoma, we need to look at more tailored forms of treatment than we currently have. The results with medicines targeting specific DNA changes have been rather disappointing so far. Our study lays an important foundation for developing better ways to tailor treatment to children’s specific form of rhabdomyosarcoma, and for future developments in immunotherapy for these patients” says Oncode Investigator Jarno Drost.
For this study, the scientists analyzed 19 tumor samples from children with rhabdomyosarcoma treated in the Princess Máxima Center and eight mini-tumors in the lab, known as tumoroids, using single cell RNA sequencing. This allowed them to put together a detailed ‘atlas’ of the many different cell types that make up the tumors. They found that the tumor cells varied greatly in maturity, and suppressed attacks from the immune system.
“We saw immune cells called cytotoxic T-cells in the rhabdomyosarcoma tumors. These immune cells have the potential to attack the tumor cells, but they’re stopped from doing so” says Jeff DeMartino, PhD student in the Drost group.
Tumors often develop a way to dodge or put the brakes on the body’s own immune system. Reversing this immunosuppression can kickstart the immune attack and help kill the cancer cells. “Our study found a gene expressed in rhabdomyosarcoma that could explain how it puts the brakes on the immune attack,” says DeMartino. “More research is needed to untangle exactly how the tumor hijacks the immune system on a molecular level, but this work could in the future lead to possible targets for immunotherapy.”
Picking out aggressive disease
The study also found valuable clues about the maturity of cancer cells within the tumors. “We saw that the tumor cells look like normal muscle cells that are stuck in development. Not all tumor cells in each sample resembled one cell type: they differed in how far they had matured. Importantly, these differences were linked to how well children had responded to treatment” says Dr. Thanasis Margaritis, who manages the Single Cell Genomics Facility at the Princess Máxima Center and co-lead in the the study.
To confirm that the differences in cell maturity can help tell apart patients with aggressive disease from those with a good outcome, the team plans to study tumor samples from a larger group of children with rhabdomyosarcoma. They will also look for related molecular clues, and will work with their colleagues in the clinic to develop a way to apply their findings in clinical practice.
The study was recently published in Nature Communications and was funded by the Children Cancer-free Foundation.