Global immune fingerprinting in glioblastoma reveals immune-suppression signatures associated with prognosis

Abstract

Glioblastoma (GBM) remains uniformly lethal, and, despite a large accumulation of immune cells in the microenvironment, there is limited anti-tumor immune response, even with newly developed immune checkpoint therapies. To overcome these challenges and enhance the efficacy of immunotherapies, a comprehensive understanding of the immune system in GBM and changes during disease progression is required. Here, we integrated multi-parameter flow cytometry and mass cytometry time of flight (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing multi-parameter flow cytometry analysis in a cohort of over 250 patients with brain tumors ranging from benign to malignant primary and metastatic, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in blood, but not immunosuppressive T regulatory cells. We validated these findings in GBM patient tissue and found that increased numbers of MDSCs in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from a cohort of newly diagnosed GBM patients revealed that reduction in MDSC frequency over time is accompanied by a concomitant increase in dendritic cells and natural killer cells. This reduced MDSC profile was present in GBM patients with extended survival and was similar to that of lowgrade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis, either by directly targeting or by shifting the immune profile to induce differentiation toward the immune profile ofLGGs.

Insights into the glioblastoma tumor microenvironment: current and emerging therapeutic approaches

“…Regulatory T cells (Tregs) Tregs, for example, have been demonstrated to promote glioblastoma development by inhibiting the anti-tumor immune response and establishing an immunosuppressive milieu (Berghoff et al, 2017). Effector T cells, on the other hand, have the ability to recognize and eliminate tumor cells but are frequently functionally impaired within the glioblastoma microenvironment due to factors such as the upregulation of immune checkpoint molecules and the accumulation of immunosuppressive cells (Alban, 2018).…”

Deciphering immune microenvironment and cell evasion mechanisms in human gliomas

“…• Reduced antigen-presenting cells and NK cells are found in GBM patients, which are an indication of a diminished anti-tumor response (58).…”

Glycomaterials to Investigate the Functional Role of Aberrant Glycosylation in Glioblastoma

“…[40][41][42][43][44][45][46][47] Immunosuppressive regulatory T cells (Tregs) found in close proximity to other lymphocytes around GBM, carry inhibitory ligands, and prevent cytotoxic T-cell proliferation. [48][49][50][51][52][53][54][55][56][57][58] While the heterogeneous cellular composition and secreted factors in the TME that contribute to GBM growth have been extensively reviewed elsewhere, [14][15][16][17][20][21][22]32,33] there is a general lack of insight into the significant roles of cellular and extracellular glycans in regulating cell signaling and GBM progression.…”