ABSTRACT
Glioblastoma develops an immunosuppressive microenvironment that fosters tumorigenesis and resistance to current therapeutic strategies. Here we use multiplexed tissue imaging and single-cell RNA-sequencing to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioblastoma. We show that glioblastoma exhibit strong expression of CD39 and CD73 ectoenzymes, correlating with increased adenosine levels. Microglia are the predominant source of CD39, while CD73 is principally expressed by tumor cells, particularly in tumors with amplification of EGFR and astrocyte-like differentiation. Spatially-resolved single-cell analyses demonstrate strong spatial correlation between tumor CD73 and microglial CD39, and that their spatial proximity is associated with poor clinical outcomes. Together, this data reveals that tumor CD73 expression correlates with tumor genotype, lineage differentiation, and functional states, and that core purine regulatory enzymes expressed by neoplastic and tumor-associated myeloid cells interact to promote a distinctive adenosine-rich signaling niche and immunosuppressive microenvironment potentially amenable to therapeutic targeting.
Competing Interest Statement
SS is a consultant for RareCyte Inc. MT has a consulting or advisory role with Agios Pharmaceutical, Integragen, and Taiho Oncology, and research funding from Sanofi. PKS is a member of the SAB or BOD member of Applied Biomath, RareCyte Inc., and Glencoe Software, which distributes a commercial version of the OMERO database; PKS is also a member of the NanoString SAB. In the last five years the Sorger lab has received research funding from Novartis and Merck. KLL is supported by Eli Lilly and BMS, consults for BMS, Integragen, Travera LLC, is on the SAB of Integragen and Rarecyte, and holds equity in Travera LLC. PB receives grant funding from Novartis Institute of Biomedical Research and Deerfield, and consults for QED Therapeutics, for unrelated projects. PW has research support from Agios, Astra Zeneca, Medimmune, Celgene, Eli Lilly, Genentech, Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Chimerix, Vascular Biogenics, and VBI Vaccines. PW is on the advisory boards of Agios, Astra Zeneca, Black Diamond, Boston Pharmaceuticals, Chimerix, CNS Pharmaceuticals, Elevate Bio, Imvax, Karyopharm, Merck, Mundipharma, Novocure, Novartis, Nuvation Bio, Prelude Therapeutics, Vascular Biogenics, VBI Vaccines, Voyager, and QED. PKS and SS declare that none of these relationships have influenced the content of this manuscript.
