Coordinated Regulation of Myeloid-Derived Suppressor Cells by Cytokines and Chemokines
Abstract
:Simple Summary
Abstract
1. Introduction
2. Regulation of MDSC Expansion by Cytokines and Chemokines
3. Recruitment of MDSCs to TME
4. Immunosuppression Effects of MDSCs
5. Cytokines/Chemokines Regulating Neutrophils and Monocytes in Cancer
5.1. Neutrophils
5.1.1. The Anti-Tumor Role of Neutrophils
5.1.2. The Tumor-Promoting Role of Neutrophils
5.2. Monocytes
6. Therapies Targeting MDSCs in Cancer Treatment
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Arg-1 | arginase 1 |
CSFs | colony-stimulating factors |
CCL2 | C-C motif chemokine ligand 2 |
CCL5 | C-C motif ligand 5 |
CCR2 | C-C chemokine receptor type 2 |
CXCR2 | C-X-C motif chemokine receptor 2 |
EMT | epithelial–mesenchymal transition |
G-CSF | granulocyte colony-stimulating factor |
GM-CSF | granulocyte/macrophage colony-stimulating factor |
HIF1α | hypoxia-inducible factor 1-alpha |
HGF | hepatocyte growth factor |
IL-1β | interleukin-1beta |
IL-6 | interleukin-6 |
iNOS | inducible NO synthase |
IFN-I | type I interferons |
IL-4Rα | interleukin-4 receptor alpha |
MDSCs | myeloid-derived suppressor cells |
M-MDSCs | monocytic MDSCs |
M-CSF | macrophage colony-stimulating factor |
MMP | matrix metalloproteinase |
Nox2 | NADPH oxidase |
NO | nitric oxide |
Nos2 | nitric oxide synthase 2 |
N1 | tumor-suppressing neutrophils |
N2 | tumor-promoting neutrophils |
NETs | neutrophil extracellular traps |
PMN-MDSCs | polymorphonuclear MDSCs |
PNT | peroxynitrite |
PDAC | pancreatic ductal adenocarcinoma cell |
PyMT | polyoma Middle T |
PGE2 | prostaglandin E2 |
PDE5 | phosphodiesterase type 5 |
TNFα | tumor necrosis factor α |
TME | tumor microenvironment |
TGFβ | transforming growth factor beta |
TAM | tumor-associated macrophages |
ROS | reactive oxygen species |
RTK | receptor tyrosine kinases |
STAT3 | signal transducer and activator of transcription 3 |
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Types of MDSCs | Human | Mice |
---|---|---|
PMN-MDSC | CD11b+CD14−CD15+, CD11b+CD14−CD66b+ [3] LIN−CD11b+HLA-DR−CD33+, LIN−CD11b+HLA-DR−CD66b+, LIN−CD11b+HLA-DR−CD15+, LIN−CD11b+HLA-DR−CD15+CD66b+ [4] CD11b+CD14-CD33+ (additionally CD15 and/or CD66b) [4] CD11b+HLA-DR−CD15+CD14−CD33mid [5] | CD11b (+)Ly6G(+)Ly6C(low) [3,5] CD11b+GR1hiLY6ClowLY6G+CD49d− [4] |
M-MDSC | CD11b+CD14+HLA-DR−/lowCD15− [3] CD33+CD14+HLA-DRlow/− [4] CD11b+HLA-DR−CD15−CD14+CD33hi [5] | CD11b(+)Ly6G(−)Ly6C (high) [3,5] CD11b+GR1midLY6ChiLY6G−CD49d+ [4] |
Strategy | Drugs/Chemokines | Mechanism |
---|---|---|
Inducing MDSC Differentiation | Inhibiting the molecular mechanisms targeting Arg-1, iNOS, and STAT3 activities | Deactivating MDSC immunosuppressive functions on T cell activity. |
Targeting MDSC activity | Sunitinib (a small-molecule, synthetic indoline-based receptor tyrosine kinase (RTK) inhibitor) | Decreasing the suppressive function of M-MDSCs by reducing their expression of Arg-1 and phosphorylated STAT3/increasing T cell proliferative activity/improving progression-free survival/in high-risk non-muscle invasive bladder cancer, sunitinib can resolve MDSC-mediated immunosuppression. |
Tadalafil (phosphodiesterase type 5 (PDE5) inhibitor) | Decreasing the expression of IL-4Rα, resulting in the reduction of the phosphorylation of STAT6 and Arg-1 expression to effectively block MDSC functions/a clinical trial has proven the reduction of MDSC and Treg/increasing tumor-specific CD8+ T cells. | |
MDSC depletion | Using systemic chemotherapeutic agents such as gemcitabine, 5-fluorouracil, paclitaxel [62], and gemcitabine [63] | Reducing the numbers and effectiveness of MDSCs in the TME using animal models/in combination with other drugs, has shown decreased density of MDSC, leading to the restoration of immune functions and tumor regression/low-dosage chemotherapeutic treatment with paclitaxel, gemcitabine was found to deplete MDSC populations and improve anti-tumor immune action in mice model. |
Blocking MDSC recruitment and trafficking | Drugs developed against inflammatory cytokines, including a human monoclonal antibody carlumab for CCL2, a selective CCR2 antagonist (PF-04136309), a CCR5 antagonist (Maraviroc), and a small-molecule CSF-1R inhibitor (Pexidartinib) | Effectively blocking the chemokine receptors present on MDSCs due to ligand redundancy, as these chemokines play an important role in the recruitment of MDSCs. |
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Li, R.; Mukherjee, M.B.; Lin, J. Coordinated Regulation of Myeloid-Derived Suppressor Cells by Cytokines and Chemokines. Cancers 2022, 14, 1236. https://doi.org/10.3390/cancers14051236
Li R, Mukherjee MB, Lin J. Coordinated Regulation of Myeloid-Derived Suppressor Cells by Cytokines and Chemokines. Cancers. 2022; 14(5):1236. https://doi.org/10.3390/cancers14051236
Chicago/Turabian StyleLi, Ru, Mousumi Beto Mukherjee, and Jun Lin. 2022. "Coordinated Regulation of Myeloid-Derived Suppressor Cells by Cytokines and Chemokines" Cancers 14, no. 5: 1236. https://doi.org/10.3390/cancers14051236