Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

Shannon Coy, Shu Wang, Sylwia A. Stopka, Jia-Ren Lin, Clarence Yapp, Cecily C. Ritch, Lisa Salhi, Gregory J. Baker, Rumana Rashid, Gerard Baquer, Michael Regan, Prasidda Khadka, Kristina A. Cole, Jaeho Hwang, Patrick Y. Wen, Pratiti Bandopadhayay, Mariarita Santi, Thomas Raedt, Keith L. Ligon, Nathalie Y. R. Agar, Peter K. Sorger, Mehdi Touat () and Sandro Santagata ()
Additional contact information
Shannon Coy: Harvard Medical School
Shu Wang: Harvard Program in Therapeutic Science
Sylwia A. Stopka: Harvard Medical School
Jia-Ren Lin: Harvard Program in Therapeutic Science
Clarence Yapp: Harvard Program in Therapeutic Science
Cecily C. Ritch: Harvard Medical School
Lisa Salhi: and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix
Gregory J. Baker: Harvard Program in Therapeutic Science
Rumana Rashid: Harvard Medical School
Gerard Baquer: Harvard Medical School
Michael Regan: Harvard Medical School
Prasidda Khadka: Dana-Farber Boston Children’s Cancer and Blood Disorders Center
Kristina A. Cole: University of Pennsylvania
Jaeho Hwang: Harvard Medical School
Patrick Y. Wen: Brigham and Women’s Hospital, Harvard Medical School
Pratiti Bandopadhayay: Dana-Farber Boston Children’s Cancer and Blood Disorders Center
Mariarita Santi: Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
Thomas Raedt: University of Pennsylvania
Keith L. Ligon: Harvard Medical School
Nathalie Y. R. Agar: Harvard Medical School
Peter K. Sorger: Harvard Program in Therapeutic Science
Mehdi Touat: and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix
Sandro Santagata: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-24

Abstract: Abstract How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

Date: 2022
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DOI: 10.1038/s41467-022-32430-w

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