Myeloid-derived suppressor cell

MDSC (myeloid-derived suppressor cells) are a heterogenous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells).

MDSCs strongly expand in pathological situations such as chronic infections and cancer, as a result of an altered haematopoiesis.[1] MDSCs are discriminated from other myeloid cell types in which they possess strong immunosuppressive activities rather than immunostimulatory properties. Similar to other myeloid cells, MDSCs interact with other immune cell types including T cells, dendritic cells, macrophages and natural killer cells to regulate their functions. Although their mechanisms of action are not clear yet, clinical and experimental evidence has shown that cancer tissues with high infiltration of MDSCs are associated with poor patient prognosis and resistance to therapies.[2][3][4][5] MDSCs can also be detected in the blood. In breast cancer patients, MDSC levels in the blood are about 10-fold higher than normal.[6]

It is yet unclear whether MDSCs represent a group of immature myeloid cell types that have stopped their differentiation, or they represent a distinctive myeloid lineage.

Phenotype

In mice

In mouse models, MDSCs are found as myeloid cells expressing high levels of CD11b (a classical myeloid lineage marker) and GR1 (granulocytic marker). The GR1 marker is made up of two cell membrane molecules, Ly6C and Ly6G, and according to their relative expression levels murine MDSCs are further classified into two subtypes, monocytic and granulocytic. Monocytic MDSCs express high levels of the Ly6C surface marker with low or no expression of the Ly6G marker, while granulocytic MDSCs express Ly6C and high levels of Ly6G. These phenotypes are reminiscent of those from inflammatory monocytes (and hence the term "monocytic MDSC") and granulocytes (for "granulocytic MDSCs), respectively.

In humans

Human MDSCs are less characterized, and they are generally defined as myeloid cells expressing CD33, CD14 and low levels of HLA DR. The absence of the human equivalent to the murine GR1 marker makes it difficult to compare murine and human MDSCs. Although they functionally resemble murine MDSCs, their characterization and classification into different subsets remains to be resolved as there is (As of 2012) no international consensus on how human subsets of MDSC should be defined.[7] However, A combination of CD33 and CD15 has been found to identify two major subsets of the MSDC in the peripheral blood of bladder cancer patients into granulocyte-type CD15(high) CD33(low) cells and monocyte-type CD15(low) CD33(high) cells.[8][9]

Production and activity

Generally speaking, regardless of whether they are from mice or human, MDSC suppressor function lies in their ability to inhibit T cell proliferation and activation. In healthy individuals, immature myeloid cells formed in the bone marrow differentiate to dendritic cells, macrophages and neutrophils. However, under chronic inflammatory conditions (viral and bacterial infections) or cancer, myeloid differentiation is skewed towards the expansion of MDSCs. These MDSCs infiltrate inflammation sites and tumors, where they stop immune responses by inhibiting T cells and NK cells, for example. MDSCs also accelerate angiogenesis, tumor progression and metastasis through the expression of cytokines and factors such as TGF-beta. Therefore, they have become a key therapeutic target.

MDSC differentiation

In humans

MDSCs derive from bone marrow precursors usually as the result of a perturbed myeloipoiesis caused by different pathologies. In cancer patients, growing tumours secrete a variety of cytokines and other molecules which are key signals involved in the generation of MDSC. Tumor cell lines overexpressing colony stimulating factors (e.g. G-CSF and GM-CSF) have long been used in in vivo models of MDSC generation. GM-CSF, G-CSF and IL-6 allow the in vitro generation of MDSC that retain their suppressive function in vivo. In addition to CSF, other cytokines such as IL-6, IL-10, VEGF, PGE2 and IL-1 have been implicated in the development and regulation of MDSC.[2][10] The myeloid-differentiation cytokine GM-CSF is a key factor in MDSC production from bone marrow,[11] and it has been shown that the c/EBPβ transcription factor plays a key role in the generation of in vitro bone marrow-derived and in vivo tumor-induced MDSC. Moreover, STAT3 promotes MDSC differentiation and expansion and IRF8 has been suggested to counterbalance MDSC-inducing signals.

In mice

Murine MDSCs show two distinct phenotypes which discriminate them into either monocytic MDSCs or granulocytic MDSCs. The relationship between these two subtypes remains controversial, as they closely resemble monocytes and neutrophils respectively. While monocyte and neutrophil differentiation pathways within the bone marrow are antagonistic and dependent on the relative expression of IRF8 and c/EBP transcription factors (and hence there is not a direct precursor-progeny link between these two myeloid cell types), this seems not to be the case for MDSCs. Monocytic MDSCs seem to be precursors of granulocytic subsets demonstrated both in vitro and in vivo.[11][12] This differentiation process is accelerated upon tumour infiltration and possibly driven by the hypoxic tumor microenvironment.

Activity/function

MDSC activity was originally described as suppressors of T cells, in particular of CD8+ T-cell responses. The spectrum of action of MDSC activity also encompasses NK cells, dendritic cells and macrophages. Suppressor activity of MDSC is determined by their ability to inhibit the effector function of lymphocytes. Inhibition can be caused different mechanisms. It is primarily attributed to the effects of the metabolism of L-arginine. Another important factor influencing the activity of MDSC is oppressive ROS.[2][13]

MDSC inhibitors

In addition to host-derived factors, pharmacologic agents also have profound impact on MDSC. Chemotherapeutic agents belonging to different classes have been reported to inhibit MDSC. Although this effect may well be secondary to inhibition of hematopoietic progenitors, there may be grounds for search of selectivity based on long-known differential effects of these agents on immunocompetent cells and macrophages.[2] In 2015, MDSCs were compared to immunogenic myeloid cells highlighting a group of core signaling pathways that control pro-carcinogenic MDSC functions.[14] Many of these pathways are known targets of chemotherapy drugs with strong anti-cancer properties.

As of May 2018 there are no FDA approved drugs developed to target MDSCs but experimental INB03 has entered early clinical trials.[15][16]

There is promising evidence for inhibiting Galectin-3 as a therapeutic target to reduce MDSCs.[17][18] In a Phase 1b clinical trial of GR-MD-02 developed by Galectin Therapeutics, investigators observed a significant decrease in the frequency of suppressive myeloid-derived suppressor cells following treatment in responding melanoma patients.[19]

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References
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  3. Allavena P, Mantovani A (February 2012). "Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment". Clinical and Experimental Immunology. 167 (2): 195–205. doi:10.1111/j.1365-2249.2011.04515.x. PMC 3278685. PMID 22235995.
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  15. INmune Bio Initiates Phase I Clinical Trial Of INB03 May 2018
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  19. Galectin Therapeutics Inc. (2018-09-20). "Positive Preliminary Results from Phase 1b Clinical Trial of GR-MD-02 and KEYTRUDA® in Advanced Melanoma and Expansion of the Trial". GlobeNewswire News Room. Retrieved 2019-03-14.
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