Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma

Sakthi Rajendran; Yang Hu; Alessandro Canella; Clayton Peterson; Amy Gross; Maren Cam; Matthew Nazzaro; Abigail Haffey; Akdes Serin-Harmanci; Rosario Distefano; Giovanni Nigita; Wesley Wang; Daniel Kreatsoulas; Zihai Li; Jesse A Sepeda; Andrew Sas; Mark E Hester; Katherine E Miller; Olivier Elemento; Ryan D Roberts; Eric C Holland; Ganesh Rao; Elaine R Mardis; Prajwal Rajappa

doi:10.1016/j.celrep.2023.112197

Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma

Cell Rep. 2023 Mar 28;42(3):112197. doi: 10.1016/j.celrep.2023.112197. Epub 2023 Mar 3.

Authors

Sakthi Rajendran¹, Yang Hu², Alessandro Canella¹, Clayton Peterson¹, Amy Gross³, Maren Cam³, Matthew Nazzaro¹, Abigail Haffey¹, Akdes Serin-Harmanci⁴, Rosario Distefano⁵, Giovanni Nigita⁵, Wesley Wang⁶, Daniel Kreatsoulas⁷, Zihai Li⁷, Jesse A Sepeda⁸, Andrew Sas⁸, Mark E Hester⁹, Katherine E Miller¹, Olivier Elemento², Ryan D Roberts³, Eric C Holland¹⁰, Ganesh Rao⁴, Elaine R Mardis¹¹, Prajwal Rajappa¹²

Affiliations

¹ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
² Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
³ Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
⁴ Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁶ Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁷ Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁸ Department of Neurology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Neuroscience Research Institute, The Ohio State University, Columbus, OH, USA.
⁹ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Neurology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹⁰ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹¹ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹² The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address: prajwal.rajappa@nationwidechildrens.org.

PMID: 36871221
DOI: 10.1016/j.celrep.2023.112197

Abstract

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4⁺ and CD8⁺ T cells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression.

Keywords: CD74; CP: Cancer; CP: Neuroscience; MHCII; glioblastoma; immunosuppressive TME; low-grade glioma; malignant progression; myeloid cells; single-cell RNA sequencing.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
CD8-Positive T-Lymphocytes / pathology
Disease Models, Animal
Glioma* / genetics
Glioma* / pathology
Macrophages / pathology
Mice
Sequence Analysis, RNA
Tumor Microenvironment

Grants and funding

U54 CA232561/CA/NCI NIH HHS/United States