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Myeloid-derived Suppressor Cells (MDSC)


Introduction of Myeloid-derived Suppressor Cells

In addition to surgical resection, radiation therapy and chemotherapy, immune system has been studied to use the treatment of tumors. Many tumor cells have special antigens that distinguish it from normal cells. Activated immune cells are able to recognize these antigens and then remove them. Many methods of tumor immunotherapy that have been successful in experimental animals have been used in clinical trials, but only some of them have produced certain clinical effects, and most of them have no obvious effect. The failure of these tumor vaccines or immunotherapy methods has made us wonder whether a cell is destroying the anti-tumor immune effect. In recent years, researchers have found that there is a significant increase in the number of cells in cancer patients. They are myeloid-derived suppressor cells (MDSC). MDSC can inhibit the immune system in a variety of ways, thereby promoting tumor growth and immunotherapy tumor failure.

As early as the 1980s, scholars discovered that there is a group of immunosuppressive cells that can block T cell stimulation, previously known as myeloid suppressor cells or immature myeloid cells. In 2007, Gabrilovich, etc. suggest that uniformly name MDSC. MDSC is a group of immature bone marrow cells, including immature DCs, macrophages, and neutrophils. Therefore, MDSC exhibits heterogeneity, immatureness, and plasticity. MDSC surface markers are numerous and complex, and their characteristics mainly depend on the influence of different cytokines in the body and the source of cells. Different sources of cytokines, such as GM-CSF, VEGF, IL-1B, IL-6, prostaglandins, etc., can mobilize hematopoietic precursor cells in the bone marrow into MDSCs with immunosuppressive effects. Previous studies have shown the presence of MDSC in both patients with tumors and in mice. In addition, when the body is infected by microorganisms or parasites, chemotherapy, induced autoimmunity or stress, the expression of cytokines will improve the number of MDSCs. It mainly expresses Gr-1+ and CDllb+ in mice, but expresses CD34+, CD33+ and CDl5 in human body. None of the mature bone marrow cell markers is expressed. According to the expression of Gr-1 and morphological differences, it can be divided into two groups: polymorphonuclear cells (CDlIb+ Gr-1 (high)) and monocytes (CDllb+ Gr-1 (low)). The former inhibits the process that CD8+ T cells produce interferon-1 (IFN-1) by reactive oxygen species. The latter inhibits T cell activity by a nitric oxide (NO) -dependent manner. Interestingly, here is no difference in immunosuppressive power between the two. MDSC polymorphonuclear cell subsets can influence the differentiation direction of monocyte subsets by secreting cytokines.

MDSC is often associated with tumors. Cytokines are produced by tumors and their infiltrating cells. The cytokines include vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, IL-6, IL-10, IL-13 and so on. They will influence the Janus kinase signaling pathway and transcriptional activator pathway of bone marrow precursor cells, and then blocks the differentiation of bone marrow precursor cells into mature cell lines, resulting in the accumulation of a large number of Gr-1+CD11b+ cells in the blood, spleen and tumor tissues, and these MDSCs show an immunosuppressive phenotype. Recent studies have shown that bone marrow-associated protein S100A9, which can be induced by signal transduction and transcriptional activator 3, can also increase MDSC aggregation. Gr-1+CD11b+ cells are also present in normal individuals, but they are sparsity and do not have the suppressive function in tumor diseases. It has been experimentally demonstrated that after exogenous injection of GM-CSF and VEGF, MDSC aggregation also occurs in normal mice, and after the addition of IL-13, the cells begin to exhibit inhibitory activity. In addition to neoplastic disease, MDSC can accumulate in the presence of trauma, infection, exposure to super-antigen, and even in the use of recombinant vaccines. However, there is still a difference between MDSC in non-neoplastic diseases and tumor diseases. The former returns to normal after exogenous stimuli are removed, and the latter persists. MDSC also has plasticity, and its biological characteristics can change with changes in the environment. Under the action of Th2 cytokines, such as IL-4, IL-10, MDSC enhances the expression of immunosuppressive enzymes. Under the action of Th1 cytokines, such as IFN-γ, MDSC can enhance specific T cell function.

Myeloid-derived suppressor cells

The Mechanism of MDSC in Suppressing Immunity

The inhibitory function and mechanism of MDSC are not completely consistent in different tumor models and experimental environments, but the basic inhibition pathways have similarities. The mechanism can be divided into two categories: amino acid dependent and non-dependent pathways. The amino acid dependent pathway mainly affects tumor immunity by regulating amino acid metabolism. For example, the arginase-1(ARG-1) contained in MDSC can reduce the amount of L-arginine, so that the expression of CD3ζ is reduced, the decrease will impair the function of T cells. In addition, MDSC also contains activity of the inducible nitric oxide synthase (iNOS). It can produce NO which blocks T cell responses; indoleamine 2,3 dioxygenase(IDO) can be produced by tumor cells, dendritic cells, and mononuclear cells. It can produce toxic metabolites by the consumption of tryptophan, and induces regulatory T cells to inhibit tumor immunity; MDSC induces L-amino acid oxidase 1 by IL-4, which promotes the deamination of phenylalanine and the production of hydrogen peroxide. Hydrogen peroxide affects the expression of CD3ζchains and the proliferation of T cells; MDSC also inhibits T cell proliferation by reducing the amount of cysteine in the internal environment. For non-amino acid metabolism-dependent immunosuppression, MDSC can inhibit the function of T cells by secreting immunosuppressive cytokines such as transforming growth factor-β (TGF-β), IL-10.

MDSC Related Immunotherapy

Researchers have tried to block MDSC-mediated immunosuppression in a variety of ways, including: 1 using anti-Gr-1 antibody scavenging Gr-1+ cells, but Gr-1 is not uniquely expressed in MDSC, but also expressing in neutrophils; 2 inducing mature differentiation of MDSC; 3 using the specific blockers or scavengers to block the activity of NOS and ARG; 4 changing microenvironment of tumor growth. However, due to the unclear details of the phenotype and function involved in the induction of immune tolerance by MDSC, there are still many problems in the clinical application of MDSC to require further research.

References:

  1. Gabrilovich DI., et al. The terminology issue for myeloid—derived suppressor ceHs. Cancer Res. 2007, 67(1): 425-425.
  2. Marigo I., et al. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008, 222: 162-179.
  3. Serafini P., et al.Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother. 2004, 53(2): 64-72.
  4. Serafini P., et al. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol. 2006, 16(1): 53—65.
  5. Sica A., Bronte V., Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007, 117(5): 1155-1166.
  6. Kusmartsev S., Gabrilovieh DI., Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer lmmunol Immunother. 2006, 55(3): 237-245.
  7. Heng P., et al. Inhibition of dendritic cell differentiation and accumulation of myeloid—derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008, 205(10): 2235—2249.
  8. Bronte V., Zanovello P., Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 2005, 5(8): 641-654.

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