Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma
Authors:Woong-Jai Won1, Jessy S. Deshane2, Jianmei W. Leavenworth3, Claudia R. Oliva4 and Corinne E. Griguer4
1 Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
2 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
3 Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
4 Free Radical and Radiation Biology Program, The University of Iowa, Iowa City, IA 52242, USA.
Keywords:
glioblastoma, MDSCs, metabolic reprogramming, temozolomide (TMZ), immunotherapy.
Abbreviations:
ATRA – all-trans retinoic acid,
BBB – blood brain barrier,
BM – bone marrow, CCL – chemokine (C-Cmotif) ligand,
CCR – chemokine (C-Cmotif) receptor,
CNS – central nervous system,
COX – cyclooxygenase, DC – dendritic cell,
e-MDSC – early stage MDSC,
FA – fatty acid,
FAO – FA oxidation,
GAMM – glioma-associated microglia/macrophages,
GB – glioblastoma,
GBM – glioblastoma multiforme,
GEM – genetically modified,
GSC – glioma stem cell,
iNOS – inducible nitric oxide synthase,
KIR – killer cell immunoglobulin-like receptor,
LAL – lysosomal acid lipase,
MDSC – myeloid-derived suppressor cell,
MHC – major histocompatibility complex,
MIF – macrophage migration inhibitory factor,
MMP – matrix metalloproteinase,
mTOR – mechanistic target of rapamycin,
NK – natural killer,
NSG – nod, scid, gamma,
OXPHOS – oxidative phosphorylation,
PMN – polymorphonuclear,
RNS – reactive nitrogen species,
ROS – reactive oxygen species,
SCF – stem cell factor,
TAM – tumor associated macrophage,
Tc – cytotoxic T cell,
TCA – tricarboxylic acid,
TCR – T cell receptor,
TME – tumor microenvironment,
Treg – regulatory T cell,
TMZ – temozolomide,
VEGF – vascular endothelial growth factors,
WHO – world health organization.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of financial interests.
Please cite this article as:
Woong-Jai Won, Jessy S. Deshane, Jianmei W. Leavenworth, Claudia R. Oliva and Corinne E. Griguer (2019). Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma. Cell Stress 3(2): 48-65. doi: 10.15698/cst2019.02.176
© 2019 Won et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Glioblastoma, also known as glioblastoma multiforme, 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 reprogramming 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.