Results from a new study by scientists from Cedars-Sinai Cancer show that tumors called from soft-tissue sarcomas produce a protein that switches immune cells from tumor-attacking to tumor-promoting.

Jlenia Guarnerio, MS, Ph.D., a molecular and cellular biologist trained at Harvard Medical School who currently holds academic appointments as a research scientist and assistant professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai and David Geffen School of Medical at UCLA. Photo courtesy: © 2021 – 2022 Cedars-Sinai Cancer. Used with permission.

The study, funded by the National Institutes of Health, the Sarcoma Foundation of America, and Cedars-Sinai Cancer, and published in the peer-reviewed journal Cell Reports, could lead to improved treatments for soft-tissue sarcomas.[1]

In their study, the scientists focused on the tumor microenvironment-an ecosystem of blood vessels and other cells recruited by tumors to supply them with nutrients and help them survive.

“Tumors also recruit immune cells,” explained Jlenia Guarnerio, MS, Ph.D., a molecular and cellular biologist trained at Harvard Medical School who currently holds academic appointments as a research scientist and assistant professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai and David Geffen School of Medical at UCLA.

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In her scientific career, Guarnerio has been researching the cell-autonomous and non-cell-autonomous contributions to cancer and has focused her investigations specifically on leukemia and sarcoma. She is also the main author of the study.

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“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 actually do the opposite.”

Soft-tissue sarcoma
Soft-tissue sarcoma is a rare type of cancer that forms in the muscle, fat, blood vessels, nerves, tendons, and joint lining. It most commonly occurs in the arms, legs, and abdomen, killing more than 5,000 people in the U.S. annually, according to the American Cancer Society.[2]

The most common types of sarcoma in adults include undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma), liposarcoma, and leiomyosarcoma.  Some soft-tissue sarcoma subtypes are aggressive with poor response to systemic therapies.[2]

Stephen L. Shiao, MD, Ph.D., is an Associate Professor, Radiation Oncology & Biomedical Sciences, Division Director, Division of Radiation Biology and Co-Program Leader, Translational Oncology Program for Cedars-Sinai Cancer. Photo courtesy: © 2021 – 2022 Cedars-Sinai Cancer. Used with permission.

Diagnosis and treatment
Interventional radiology plays an important role in the diagnosis, with image-guided percutaneous core needle biopsy being the most commonly used biopsy technique in the diagnosis of sarcomas. The disease must be managed by multimodality treatment in expert clinical centers where percutaneous image-guided treatments with ablation technologies (radiofrequency ablation, cryotherapy, microwaves ablation) provide a high rate of durable local control for small-sized malignant deposits in many organs including lung, liver, and bones.[3]

However, the current standard of care is unsuccessful to treat recurrent and aggressive soft-tissue sarcomas, resulting in a major unmet medical need. And while novel interventions aimed at targeting components of the tumor microenvironment have shown promise for the potential treatment of various solid tumors, this approach has only been marginally tested for sarcoma because of knowledge of the composition of the sarcoma microenvironment remains limited.

Microenvironment
In comparing samples of a variety of soft-tissue sarcomas in humans and laboratory mice, Guarnerio and her team noted that most of these tumors have an abundance of immune cells called myeloid cells in their microenvironment.

In their study, the scientists single-cell RNA sequencing to characterize the immune composition of an undifferentiated pleiomorphic sarcoma mouse model, showing that macrophages in the sarcoma mass exhibit distinct activation states. Sarcoma cells use the pleiotropic cytokine macrophage migration inhibitory factor (MIF), an inflammatory cytokine that serves many roles in inflammation and immunity and is involved in carcinogenesis, to interact with macrophages expressing the Cluster of differentiation 74 (CD74) receptor to switch macrophages’ activation state and pro-tumorigenic potential. [1][4]

Data show that MIF is overexpressed in various malignancies in humans, and contributes to the deregulation of the cell cycle, angiogenesis, and metastasis. Other studies show that MIF overexpression in these types of tumors significantly decreases survival rate, and increases tumor aggression.

Myeloid cells
“It was striking that such a large percentage of the immune cells were myeloid cells, and we thought that since they obviously weren’t killing the tumor cells, they must be doing something to promote tumor growth,” said Stephen Shiao, MD, Ph.D., division director of the Division of Radiation Biology, co-leader of the Translational Oncology Program and a co-author of the study.

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

Study design
To find out what was causing this change, investigators 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 cross-talk between these two populations of cells,” 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 sense the MIF proteins. This makes them switch their biology and promote, rather than block, tumor growth,” Shiao explained.

When the investigators generated tumors from cancer cells that didn’t express MIF, myeloid cells were able to penetrate the tumors, and tumor growth was reduced.

“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 noted.

New therapies
The researchers believe that blocking the expression of MIF in sarcoma cells favors the accumulation of macrophages with inflammatory and antigen-presenting profiles, reducing tumor growth.

Dan Theodorescu, MD, Ph.D., is PHASE ONE Foundation, Distinguished Chair, Director, Cedars-Sinai Cancer, Professor, Surgery and Professor, Pathology and Laboratory Medicine. Photo courtesy: © 2021 – 2022 Cedars-Sinai Cancer. Used with permission.

This understanding may pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care. based on this investigators believe this information can be used to create novel therapies against soft-tissue sarcoma.

A medication designed to stop 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 proved resistant to our existing therapies,” said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer.

“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.”

CD74 could be used as a potential target for treatment and as a biomarker to predict the prognosis of patients.

Future studies
Guarnerio plans to pursue these investigations and begin addressing many additional 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.

“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,” she concluded.

Reference
[1] Tessaro FHG, Ko EY, De Simone M, Balzer B, Shiao SL, Guarnerio J. Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity. Cell Reports. DOI 10.1016/j.celrep.2022.110977
[2] Key Statistics for Soft Tissue Sarcomas. American Cancer Society. Online. Last accessed on June 21, 2022.
[3] Bourcier K, Le Cesne A, Tselikas L, Adam J, Mir O, Honore C, de Baere T. Basic Knowledge in Soft Tissue Sarcoma. Cardiovasc Intervent Radiol. 2019 Sep;42(9):1255-1261. doi: 10.1007/s00270-019-02259-w. Epub 2019 Jun 24. PMID: 31236647.
[4] Guda MR, Rashid MA, Asuthkar S, Jalasutram A, Caniglia JL, Tsung AJ, Velpula KK. Pleiotropic role of macrophage migration inhibitory factor in cancer. Am J Cancer Res. 2019 Dec 1;9(12):2760-2773. PMID: 31911860; PMCID: PMC6943360.

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