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 1

LV-contacting and -noncontacting GBMs are enriched in distinct immune subsets.

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LV-contacting and -noncontacting GBMs are enriched in distinct immune su...
(A) Representative MRI radiographs of GBM tumors with confirmed contact with either of the LVs (left, C-GBM) or lacking ventricular involvement (right, NC-GBM). Yellow line indicates the LV. Arrows indicate the tumor mass. Kaplan-Meier curve indicates the survival proportion in patients with C-GBM (n = 12) and NC-GBM (n = 13). (B) Schematic of experimental workflow. (C) Live CD45+ cells were combined from all patients (black contour, n = 19), C-GBM tumors only (red contour, n = 9), or NC-GBM tumors only (blue contour, n = 10). Overlaid t-SNE plots indicate areas of immune infiltration unique to patients with tumor subtype. Enrichment indicates which computationally gated immune populations were statistically enriched in C-GBM or NC-GBM. Heatmaps displayed for chosen markers indicate major immune subsets. (D) Bar graphs demonstrating the frequency of immune cells found within each computational cluster as a percentage of total CD45+ leukocytes. Statistical significance was calculated using a χ2 test. * = P < 0.05, ** = P < 0.01, *** = P < 0.001, **** = P < 0.0001.