Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

Fernando H G Tessaro; Emily Y Ko; Marco De Simone; Roberta Piras; Marina T Broz; Helen S Goodridge; Bonnie Balzer; Stephen L Shiao; Jlenia Guarnerio

doi:10.1016/j.celrep.2022.110977

Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

Cell Rep. 2022 Jun 21;39(12):110977. doi: 10.1016/j.celrep.2022.110977.

Authors

Fernando H G Tessaro¹, Emily Y Ko¹, Marco De Simone¹, Roberta Piras¹, Marina T Broz², Helen S Goodridge³, Bonnie Balzer⁴, Stephen L Shiao⁵, Jlenia Guarnerio⁶

Affiliations

¹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen Medical School, Department of Medicine, UCLA, Los Angeles, CA, USA.
⁶ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen Medical School, Department of Medicine, UCLA, Los Angeles, CA, USA. Electronic address: jlenia.guarnerio@cshs.org.

Abstract

The standard of care is unsuccessful to treat recurrent and aggressive soft-tissue sarcomas. Interventions aimed at targeting components of the tumor microenvironment have shown promise for many solid tumors yet have been only marginally tested for sarcoma, partly because knowledge of the sarcoma microenvironment composition is limited. We employ 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) to interact with macrophages expressing the CD74 receptor to switch macrophages' activation state and pro-tumorigenic potential. Blocking the expression of MIF in sarcoma cells favors the accumulation of macrophages with inflammatory and antigen-presenting profiles, hence reducing tumor growth. These data may pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care.

Keywords: CP: Cancer; MIF; UPS; macrophage migration inhibitory factor; sarcoma mouse models; soft tissue sarcoma; tumor inflammation; tumor microenvironment; tumor-associated macrophages; undifferentiated pleiomorphic sarcoma.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Histocompatibility Antigens Class II / genetics
Histocompatibility Antigens Class II / metabolism
Intramolecular Oxidoreductases / metabolism*
Macrophage Migration-Inhibitory Factors / genetics
Macrophage Migration-Inhibitory Factors / metabolism*
Mice
RNA-Seq
Sarcoma* / genetics
Soft Tissue Neoplasms*
Tumor Microenvironment

Substances

Histocompatibility Antigens Class II
Macrophage Migration-Inhibitory Factors
Intramolecular Oxidoreductases
MIF protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding