An immunosuppressed microenvironment distinguishes lateral ventricle–contacting glioblastomas
Todd Bartkowiak, Sierra M. Lima, Madeline J. Hayes, Akshitkumar M. Mistry, Asa A. Brockman, Justine Sinnaeve, Nalin Leelatian, Caroline E. Roe, Bret C. Mobley, Silky Chotai, Kyle D. Weaver, Reid C. Thompson, Lola B. Chambless, Rebecca A. Ihrie, Jonathan M. Irish
Todd Bartkowiak, Sierra M. Lima, Madeline J. Hayes, Akshitkumar M. Mistry, Asa A. Brockman, Justine Sinnaeve, Nalin Leelatian, Caroline E. Roe, Bret C. Mobley, Silky Chotai, Kyle D. Weaver, Reid C. Thompson, Lola B. Chambless, Rebecca A. Ihrie, Jonathan M. Irish
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Research Article Immunology Oncology

An immunosuppressed microenvironment distinguishes lateral ventricle–contacting glioblastomas

Abstract

Radiographic contact of glioblastoma (GBM) tumors with the lateral ventricle and adjacent stem cell niche correlates with poor patient prognosis, but the cellular basis of this difference is unclear. Here, we reveal and functionally characterize distinct immune microenvironments that predominate in subtypes of GBM distinguished by proximity to the lateral ventricle. Mass cytometry analysis of isocitrate dehydrogenase wild-type human tumors identified elevated T cell checkpoint receptor expression and greater abundance of a specific CD32+CD44+HLA-DRhi macrophage population in ventricle-contacting GBM. Multiple computational analysis approaches, phospho-specific cytometry, and focal resection of GBMs validated and extended these findings. Phospho-flow quantified cytokine-induced immune cell signaling in ventricle-contacting GBM, revealing differential signaling between GBM subtypes. Subregion analysis within a given tumor supported initial findings and revealed intratumor compartmentalization of T cell memory and exhaustion phenotypes within GBM subtypes. Collectively, these results characterize immunotherapeutically targetable features of macrophages and suppressed lymphocytes in GBMs defined by MRI-detectable lateral ventricle contact.

Authors

Todd Bartkowiak, Sierra M. Lima, Madeline J. Hayes, Akshitkumar M. Mistry, Asa A. Brockman, Justine Sinnaeve, Nalin Leelatian, Caroline E. Roe, Bret C. Mobley, Silky Chotai, Kyle D. Weaver, Reid C. Thompson, Lola B. Chambless, Rebecca A. Ihrie, Jonathan M. Irish

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Figure 2

Differential enrichment of 5 immune phenotypes distinguish ventricle-contacting and -noncontacting GBM.

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Differential enrichment of 5 immune phenotypes distinguish ventricle-con...
(A) Citrus clustering of live CD45+ leukocytes in the tumor microenvironment of C-GBM and NC-GBM tumors revealed differential enrichment of 5 immune subsets. (B) Heatmaps of each phenotypic marker used to classify each immune subset reveal the expression levels of each immune receptor. (C) Quantification of the arcsinh-transformed expression level of each immune marker within each subset. MMI, median mass intensity. Representative t-SNE plot of all CD45+ leukocytes infiltrating a C-GBM tumor (D) or NC-GBM tumor (E). Cell density (left), FlowSOM clustering on the t-SNE axes (middle), and Citrus overlay and quantification (right) determined the relative frequency of each immune cell subset within each patient sample. In A, a regularized regression model in the Citrus analysis identified stratifying clusters (19 patients: 9 C-GBM, 10 NC-GBM). Predictive analysis of microarrays–stratified (PAM-stratified) immune clusters. An FDR < 1% (q) determined significance in all instances.