Cell Reports (Mar 2021)
Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality
- Mai T. Dang,
- Michael V. Gonzalez,
- Krutika S. Gaonkar,
- Komal S. Rathi,
- Patricia Young,
- Sherjeel Arif,
- Li Zhai,
- Zahidul Alam,
- Samir Devalaraja,
- Tsun Ki Jerrick To,
- Ian W. Folkert,
- Pichai Raman,
- Jo Lynne Rokita,
- Daniel Martinez,
- Jaclyn N. Taroni,
- Joshua A. Shapiro,
- Casey S. Greene,
- Candace Savonen,
- Fernanda Mafra,
- Hakon Hakonarson,
- Tom Curran,
- Malay Haldar
Affiliations
- Mai T. Dang
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Michael V. Gonzalez
- Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Krutika S. Gaonkar
- Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Komal S. Rathi
- Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Patricia Young
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Sherjeel Arif
- Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Li Zhai
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Zahidul Alam
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Samir Devalaraja
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Tsun Ki Jerrick To
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Ian W. Folkert
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Pichai Raman
- Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Jo Lynne Rokita
- Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Bioinformatics and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, Philadelphia, PA, USA
- Daniel Martinez
- Pathology Core, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Jaclyn N. Taroni
- Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, Philadelphia, PA, USA
- Joshua A. Shapiro
- Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, Philadelphia, PA, USA
- Casey S. Greene
- Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Candace Savonen
- Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, Philadelphia, PA, USA
- Fernanda Mafra
- Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Hakon Hakonarson
- Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Tom Curran
- Children’s Research Institute at Mercy Children’s Hospital, Kansas City, KS, USA
- Malay Haldar
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
- Journal volume & issue
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Vol. 34,
no. 13
p. 108917
Abstract
Summary: Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB.