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
View: Text | PDF
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

×

Figure 4

Immunosuppressive checkpoint receptors are enriched in ventricle-contacting GBMs.

Options: View larger image (or click on image) Download as PowerPoint
Immunosuppressive checkpoint receptors are enriched in ventricle-contact...
(A) Representative t-SNE plot (n = 19) indicating the density of all CD45+ leukocytes, FlowSOM clusters on the t-SNE axes, and overlaid immune populations with enriched expression of indicated immune markers. MEM labels indicate the cellular phenotype in which the indicated markers were differentially expressed. (B) Box-and-whisker plots indicating the arcsinh-transformed median expression values of indicated immune receptors within Citrus-identified populations (n = 19 patients). (C) Histograms of pooled patient Citrus clusters from C-GBM (red, n = 9) and NC-GBM patients (blue, n = 10). (D) Representative plots indicating the frequency of CD32+CD44+ macrophages identified by Citrus. (E and F) Representative plots demonstrating the frequency of TIGIT and PD-1 coexpression in CD4+ T cells (E) and CD8+ T cells (F) infiltrating GBM tumors. In A, a regularized regression model in the Citrus analysis identified stratifying clusters (n = 19 patients). PAM-stratified immune clusters. An FDR of 1% (q) determined significance. A 2-way ANOVA determined significance in D–F from n = 20 total patients. Bars indicate median ± IQR. * = P < 0.05.