Soft tissue sarcomas alter the biology of immune cells around tumors, promoting tumor development
Researchers at Cedars-Sinai Medical Center have found that cancerous tumors known as soft tissue sarcomas release a protein that causes immune cells to change their behavior from tumor attack to tumor promotion. The work, which was recently published in the peer-reviewed journal Cell Reports, may help treat soft tissue sarcomas more effectively.
The study focused on the ecosystem of blood vessels and other cells that tumors attract to provide them with nutrients and support their survival.
“Tumors also recruit immune cells,” said Jlenia Guarnerio, Ph.D., research scientist at Cedars-Sinai Cancer, assistant professor of radiation oncology and biomedical sciences, and lead author of the study. “These immune cells should be able to recognize and attack tumor cells, but we found that tumor cells secrete a protein that changes their biology, so instead of killing tumor cells, they actually do the opposite.”
Soft tissue sarcoma is a rare cancer that develops in muscle, fat, blood vessels, nerves, tendons, and joint lining. The American Cancer Society estimates that it kills more than 5,000 Americans each year and most often affects the arms, legs and abdomen.
Guarnerio and his colleagues found that the majority of these tumors contain an overabundance of immune cells called myeloid cells in their microenvironment when comparing samples of various soft tissue sarcomas from laboratory mice and humans.
“It was striking that such a large percentage of immune cells were myeloid cells, and we thought that since they obviously weren’t killing tumor cells, they must be doing something to promote tumor growth,” said Stephen Shiao. , MD, Ph.D., Division Director of the Division of Radiobiology, Co-Lead of the Translational Oncology Program, and Study Co-Author. “And indeed, our analysis of tumor samples showed that many myeloid cells had adopted a tumor-promoting function.”
To find out what caused this change, the researchers looked at proteins secreted by tumor cells and receptors on the surface of myeloid cells, the things cells use to communicate. “We looked at the crosstalk between these two cell populations,” Guarnerio said. “We found that tumor cells expressed high levels of a protein called macrophage migration inhibitory factor. [MIF] and that myeloid cells had receptors to detect MIF proteins. This forces them to change their biology and promote, rather than block, tumor growth.
When researchers generated tumors from cancer cells that did not express MIF, myeloid cells were able to enter the tumors and tumor growth was reduced.
“This means that the myeloid cells could have directly attacked the tumors or activated other immune cells, for example T cells, to attack the tumors,” Guarnerio said.
Researchers believe this information could be used to create new therapies for soft tissue sarcoma. A drug designed to prevent cancer cells from expressing MIF could be tested in combination with existing therapies, for example, to see if it improves patient outcomes.
“Recurrent and aggressive soft tissue sarcoma has proven resistant to our existing therapies,” said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer. “Yet interventions to target components of the tumor microenvironment, which have shown promise against many solid tumors, have only been marginally tested in soft tissue sarcoma. This work could pave the way for much more effective interventions.
Guarnerio plans to continue these investigations and begin answering many more unanswered questions about soft tissue sarcoma.
“The majority of studies in cancer biology and immunotherapy have been done on carcinoma, the most common type of cancer,” Guarnerio said. “A lot of work has been done to describe what types of immune cells infiltrate these tumors and how carcinoma cells interact with immune cells, but there is almost no research on sarcomas. We need to investigate further to understand the roles of many other cells – T cells and B cells, for example – and how all the players work together.
The research was supported by National Institutes of Health grant numbers K99/R00, CA212200, and R01 CA258265; Sarcoma Foundation of America Grant Number 2019 SFA 15-19; and by Cedars-Sinai Cancer.
Reference: “Single cell RNA-seq of a soft tissue sarcoma model reveals the critical role of tumor-expressed MIF in the formation of macrophage heterogeneity” by Fernando HG Tessaro, Emily Y. Ko, Marco De Simone, Roberta Piras, Marina T Broz, Helen S. Goodridge, Bonnie Balzer, Stephen L. Shiao, and Jlenia Guarnerio, June 21, 2022, Cell reports.