Researchers demonstrate how tumors make immune cells less effective

Cedars-Sinai Cancer Center scientists found that cancerous tumors known as soft-tissue sarcomas generate a protein that changes immune cells from tumor attacking to tumor-promoting. The findings, which were published today in the peer-reviewed journal Cell Reports, may lead to better treatment options for soft-tissue sarcomas.

The researchers concentrated on the tumor microenvironment, which is an ecosystem of blood vessels and other cells selected by tumors to supply nutrients and aid in survival.

Tumors also recruit immune cells.”

Jlenia Guarnerio PhD, Study Senior Author and Research Scientist, Cedars-Sinai Cancer Center

Guarnerio was also an assistant professor of Radiation Oncology and Biomedical Sciences.

Guarnerio adds, “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.”

Soft-tissue sarcoma is a rare form of cancer that develops in the muscles, fat, blood vessels, nerves, tendons, and joint lining. As per the American Cancer Society, it destroys more than 5,000 people in the United States each year, mostly in the arms, legs, and abdomen.

Guarnerio and her colleagues discovered that most soft-tissue sarcomas in humans and laboratory mice have plenty of immune cells called myeloid cells in their microenvironment when they compared samples of these tumors.

It was striking that such a large percentage of the immune cells were myeloid cells, and we thought that since they weren’t killing the tumor cells, they must be doing something to promote tumor growth.”

Stephen Shiao MD, PhD, Study Co-Author and Division Director, Radiation Biology, Cedars-Sinai Cancer Center

Shiao was also a co-leader of the Translational Oncology Program.

Shiao states, “And indeed, our analysis of tumor samples showed that many of the myeloid cells had adopted a tumor-promoting function.”

To determine what was causing this transformation, researchers looked at the proteins secreted by tumor cells as well as the receptors on the surface of myeloid cells—the aspects that cells use to interact.

“We examined the cross-talk between these two populations of cells. 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 sense the MIF proteins. This makes them switch their biology and promote, rather than block, tumor growth,” Guarnerio remarked.

Myeloid cells were capable of penetrating tumors created by the researchers from cancer cells that did not display MIF, and tumor growth was lowered.

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

The researchers believe that this data could be used to develop new therapies for soft-tissue sarcoma. A medication aimed at preventing cancer cells from displaying MIF, for instance, could be evaluated in conjunction with standard therapies to see if it improves patient outcomes.

“Recurrent and aggressive soft-tissue sarcoma has proved resistant to our existing therapies. Yet interventions aimed at targeting components of the tumor microenvironment, which have shown promise against many solid tumors, have been only marginally tested in soft-tissue sarcoma. This work may pave the way for much more effective interventions,” assumed Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer.

Guarnerio intends to seek these interrogations as well as to begin answering many other questions unanswered 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.

He further concludes, “Much work has been done to describe which 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 investigation so that we understand the roles of many other cells—T cells and B cells, for example—and how all the players work together.”