Dataset Information

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma.

ABSTRACT: Glioblastoma, also known as glioblastoma multi-forme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic re-programming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote angiogenesis and tumor metastasis. Glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSC) are most abundantly recruited and expanded myeloid lineage cells in glioblastoma TME and mainly lead to immunosuppression. In this review, of myeloid cells we will focus on MDSC as an important driver to induce immunosuppression in glioblastoma. Here, we review current literature on immunosuppressive functions and metabolic reprogramming of MDSCs in glioblastoma and discuss their metabolic pathways as potential therapeutic targets to improve current incurable glioblastoma treatment.

SUBMITTER: Won WJ

PROVIDER: S-EPMC6551710 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma.

Won Woong-Jai WJ Deshane Jessy S JS Leavenworth Jianmei W JW Oliva Claudia R CR Griguer Corinne E CE

Cell stress 20190123 2

Glioblastoma, also known as glioblastoma multi-forme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environme ...[more]

PMID: 31225500

Similar Datasets

Project description:BACKGROUND:The tumor microenvironment (TME) combines features of regulatory cytokines and immune cell populations to evade the recognition by the immune system. Myeloid-derived suppressor cells (MDSC) comprise populations of immature myeloid cells in tumor-bearing hosts with a highly immunosuppressive capacity. We could previously identify RIG-I-like helicases (RLH) as targets for the immunotherapy of pancreatic cancer inducing immunogenic tumor cell death and type I interferons (IFN) as key mediators linking innate with adaptive immunity. METHODS:Mice with orthotopically implanted KrasG12D p53fl/R172H Ptf1a-Cre (KPC) pancreatic tumors were treated intravenously with the RLH ligand polyinosinic-polycytidylic acid (poly(I:C)), and the immune cell environment in tumor and spleen was characterized. A comprehensive analysis of the suppressive capacity as well as the whole transcriptomic profile of isolated MDSC subsets was performed. Antigen presentation capability of MDSC from mice with ovalbumin (OVA)-expressing tumors was investigated in T cell proliferation assays. The role of IFN in MDSC function was investigated in Ifnar1-/- mice. RESULTS:MDSC were strongly induced in orthotopic KPC-derived pancreatic cancer, and frequencies of MDSC subsets correlated with tumor weight and G-CSF serum levels, whereas other immune cell populations decreased. Administration of the RLH-ligand induced a IFN-driven immune response, with increased activation of T cells and dendritic cells (DC), and a reduced suppressive capacity of both polymorphonuclear (PMN)-MDSC and monocytic (M)-MDSC fractions. Whole transcriptomic analysis confirmed an IFN-driven gene signature of MDSC, a switch from a M2/G2- towards a M1/G1-polarized phenotype, and the induction of genes involved in the antigen presentation machinery. Nevertheless, MDSC failed to present tumor antigen to T cells. Interestingly, we found MDSC with reduced suppressive function in Ifnar1-deficient hosts; however, there was a common flaw in immune cell activation, which was reflected by defective immune cell activation and tumor control. CONCLUSIONS:We provide evidence that the treatment with immunostimulatory RNA reprograms the TME of pancreatic cancer by reducing the suppressive activity of MDSC, polarizing myeloid cells into a M1-like state and recruiting DC. We postulate that tumor cell-targeting combination strategies may benefit from RLH-based TME remodeling. In addition, we provide novel insights into the dual role of IFN signaling in MDSC's suppressive function and provide evidence that host-intrinsic IFN signaling may be critical for MDSC to gain suppressive function during tumor development.

Dataset Information

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma.

Publications

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets