Description:
<jats:title>Abstract</jats:title>
<jats:p>INTRODUCTION: Extracellular purinergic signaling plays critical roles in the regulation of tumor growth and anti-tumor immunity via autocrine/paracrine binding of metabolites to receptors on neoplastic and non-neoplastic populations. Extracellular purine concentrations are principally mediated by the ectonucleotidase enzymes CD39 and CD73, which catabolize ATP to adenosine. Within the tumor microenvironment, neoplastic, immune, and stromal cells expressing these enzymes may co-localize to generate an immunosuppressive adenosine-rich niche. However, the cellular composition, spatial architecture and phenotypic properties of these tumor ecosystems and their relationship to tumor genotype have been poorly characterized.</jats:p>
<jats:p>METHODS: We quantified CD73 expression by immunohistochemistry (IHC) in a cohort of CNS tumors [meningiomas(N=222), gliomas(N=244), ependymomas(N=44), medulloblastomas(N=24), craniopharyngiomas(N=38)]. We used publicly-available single-cell RNA-seq data and 36 marker multiplexed tissue imaging (t-CyCIF) of 139 clinically and genomically annotated glioblastomas to characterize CD39 and CD73 expressing populations, define immune architecture and tumor cell states at single cell resolution, evaluate spatial correlations, and identify markers of clinical outcome. Mass spectrometry imaging (MALDI-MSI) was employed to generate spatially-resolved quantification of purine metabolite levels in glioblastoma resections (N=9).</jats:p>
<jats:p>RESULTS: IHC revealed strong CD73 expression in meningiomas and gliomas. Tumor CD73 expression was associated with poor progression-free-survival in IDH-wildtype glioblastoma (p=0.04). scRNA-seq in glioblastoma revealed that CD73 is predominantly expressed by tumor cell populations, while CD39 is predominantly expressed by monocytic (macrophage, microglial) populations. t-CyCIF showed enrichment of EGFR, Ki-67, and TP53 expression in CD73-high tumor cells at a single cell level independent of genotype, as well as significant spatial correlation between CD73 expression in tumor cells and CD39 expression in macrophages. MALDI-MSI showed significantly greater adenosine concentrations in glioblastomas with high CD73 expression. CD73 expression significantly correlated with EGFR amplification or C-terminal deletion (EGFRvIII or variants), type-II interferon signaling, and PD-L1 expression in glioblastoma.</jats:p>
<jats:p>CONCLUSIONS: Phenogenomic analysis of purinergic signaling in glioblastoma revealed correlations between CD73 expression and genotype, adenosine concentration, and clinical outcome. Spatial analysis revealed interaction between macrophages CD39 expression and tumor cell CD73 expression, suggesting that these populations may interact to suppress anti-tumor immunity. Anti-CD73 therapy may provide therapeutic benefits in glioblastoma by blunting immunosuppressive and oncogenic adenosine signaling.</jats:p>
<jats:p>Citation Format: Shannon Coy, Jia-Ren Lin, Shu Wang, Sylwia Stopka, Rumana Rashid, Jaeho Hwang, Prasidda Khadka, Philipp Euskirchen, Pratiti Bandopadhayay, Patrick Y. Wen, Peter K. Sorger, Nathalie Agar, Keith L. Ligon, Mehdi Touat, Sandro Santagata. Phenogenomic characterization of immunomodulatory purinergic signaling in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1816.</jats:p>