Protein produced by soft-tissue sarcomas makes immune cells ‘go bad’

Researchers at Cedars-Sinai Cancer have discovered that cancerous tumors called soft tissue sarcomas produce a protein that switches immune cells from tumor attacking to tumor promoting. The study, published today in the peer-reviewed journal mobile reports, could lead to better treatments for soft tissue sarcomas.

The researchers focused on the tumor’s microenvironment — an ecosystem of blood vessels and other cells recruited by tumors to provide them with nutrients and help them survive.

Tumors also recruit immune cells. These immune cells should be able to recognize and attack the tumor cells, but we found that the tumor cells secrete a protein that changes their biology, so instead of killing tumor cells, they do the opposite.”


Jlenia Guarnerio, PhD, researcher at Cedars-Sinai Cancer, assistant professor of Radiation Oncology and Biomedical Sciences, and senior author of the study

Soft tissue sarcoma is a rare cancer that forms in the muscles, fat, blood vessels, nerves, tendons and joint mucosa. It is most common in the arms, legs and abdomen, killing more than 5,000 people in the US each year, according to the American Cancer Society.

Comparing samples of different soft tissue sarcomas in humans and lab mice, Guarnerio and her team noted that most of these tumors have an abundance of immune cells called myeloid cells in their microenvironment.

“It was striking that such a large percentage of the immune cells were myeloid cells, and we thought that since they clearly didn’t kill the tumor cells, they must be doing something to promote tumor growth,” said Stephen Shiao, MD, PhD, division director. of the Division of Radiation Biology, co-leader of the Translational Oncology Program and co-author of the study. “And indeed, our analysis of tumor samples showed that many of the myeloid cells had taken on a tumor-promoting function.”

To find out what caused this change, researchers examined the proteins secreted by the tumor cells and the receptors on the surface of the myeloid cells — the elements cells use to communicate. “We examined the crosstalk between these two cell populations,” Guarnerio said. “We found that the tumor cells expressed high levels of a protein called macrophage migration inhibitory factor.” [MIF]and that the myeloid cells had receptors to detect the MIF proteins. This causes them to change their biology and promote rather than block tumor growth.”

When the researchers generated tumors from cancer cells that did not express MIF, myeloid cells were able to invade the tumors and tumor growth was reduced.

“This means that the myeloid cells attacked the tumors directly, or activated other immune cells, for example T cells, to attack the tumors,” Guarnerio said.

The researchers believe this information could be used to develop 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 outcomes for patients.

“Recurrent and aggressive soft tissue sarcoma has been shown to be resistant to our existing therapies,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer. “Yet interventions targeting 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 studies and begin to answer many additional unanswered questions about soft tissue sarcoma.

“Most studies in cancer biology and immunotherapy have been done on carcinoma, the most common form 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 continue our research so that we understand the role of many other cells. -;T- cells and B cells for example-; and how all the players work together.”

Source:

Cedars-Sinai Medical Center

Reference magazine:

Tessaro, FHG, et al. (2022) Single-cell RNA-seq from a soft tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity. Cell reports. doi.org/10.1016/j.celrep.2022.110977.

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