Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma

Abstract

To assess the accumulation of myeloid-derived suppressor cells (MDSCs) in the peripheral blood of patients with glioma and to define their heterogeneity and their immunosuppressive function. Peripheral blood mononuclear cells (PBMCs) from healthy control subjects and from patients with newly diagnosed glioma were stimulated with anti-CD3/anti-CD28 and T cells assessed for intracellular expression of interferon (IFN)-γ. Antibody staining of PBMCs from glioma patients and healthy donors (CD33, HLADR, CD15, and CD14) followed by 4-color flow cytometry analysis-defined MDSC levels in the peripheral blood. To assess the role of MDSCs in suppressing T cell IFNγ production, PBMCs were depleted of MDSCs using anti-CD33 and anti-CD15 antibody-coated beads prior to T cell stimulation. Enzyme-linked immunosorbent assays were used to assess plasma arginase activity and the level of granulocyte colony-stimulating factor (G-CSF). Patients with glioblastoma have increased MDSC counts (CD33+HLADR-) in their blood that are composed of neutrophilic (CD15(+); >60%), lineage-negative (CD15(-)CD14(-); 31%), and monocytic (CD14(+); 6%) subsets. After stimulation, T cells from patients with glioblastoma had suppressed IFN-γ production when compared with healthy, age-matched donor T cells. Removal of MDSCs from the PBMCs with anti-CD33/CD15-coated beads significantly restored T cell function. Significant increases in arginase activity and G-CSF levels were observed in plasma specimens obtained from patients with glioblastoma. The accumulation of MDSCs in peripheral blood in patients with glioma likely promotes T cell immune suppression that is observed in this patient population. Increased plasma levels of arginase and G-CSF may relate to MDSC suppressor function and MDSC expansion, respectively, in patients with glioma.

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…[23][24][25][26][27][28][29][30] It has been previously shown in human samples and experimental GBM models that MDSCs are powerful inhibitors of anti-tumor immune responses. 30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression. [32][33][34][35][36] Targeting specific mechanisms of immune suppression are critical to increasing the effectiveness of immunotherapies.…”

Myeloid Derived Suppressor Cells and Their Role in Diseases

“…shown that cancer progression can be retarded or reversed with the removal of MDSCs [82,83], more studies are needed in procuring an effective way of mitigating their suppressive effects in cancer.…”

Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells

“…[5][6][7] MDSCs express CD34, common myeloid marker CD33, macrophage/DC marker CD11b, and IL-4R␣ (CD124), but lack expression of the lineage (Lin) markers of DCs and other mature myeloid cells. 7,8 Human MDSCs are defined as CD33 ϩ Lin Ϫ HLA-DR Ϫ/low or CD33 ϩ CD14 Ϫ HLA-DR Ϫ , with recent studies demonstrating a CD14 ϩ CD11b ϩ HLA-DR low phenotype of monocytic MDSCs in melanoma, 9 prostate cancer, 10 gastrointestinal malignancies, 11 hepatocellular carcinoma, 12, 13 and glioblastoma, 14 in addition to a CD15 ϩ population of neutrophil-related immature MDSCs of similar biologic activity present in the peripheral blood. 7 MDSCs express high levels of immunosuppressive factors such as indoleamine dioxygenase (IDO), 15,16 IL-10, 8 arginase, 17,18 inducible nitric oxide synthase (NOS2), 18 nitric oxide, and reactive oxygen species, 19 and use these molecules to suppress T-cell responses, 20,21 whereas their induction of natural killer cell anergy and reduced cytotoxicity is arginase independent 12 but depends on TGF␤ 1.…”