Myeloid-derived suppressor cell

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Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the

myeloid
lineage (a family of cells that originate from bone marrow stem cells).

MDSCs expand under pathologic conditions such as chronic infection and cancer, as a result of altered haematopoiesis.[1] MDSCs differ from other myeloid cell types in that they have immunosuppressive activities, as opposed to immune-stimulatory properties. Similar to other myeloid cells, MDSCs interact with immune cell types such as T cells, dendritic cells, macrophages and natural killer cells to regulate their functions. Tumors with high levels of infiltration by MDSCs have been associated with poor patient outcome and resistance to therapies.[2][3][4][5] MDSCs can also be detected in the blood. In patients with breast cancer, levels of MDSC in blood are about 10-fold higher than normal.[6] The size of the myeloid suppressor compartment is considered to be an important factor in the success or failure of cancer immunotherapy, highlighting the importance of this cell type for human pathophysiology.[7] A high level of MDSC infiltrate in the tumor microenvironment (TME) correlates with shorter survival times of patients with solid tumors and could mediate resistance to checkpoint inhibitor therapy.[8] Studies are needed to determine whether MDSCs are a population of immature myeloid cells that have stopped differentiation or a distinct myeloid lineage.

Formation

MDSCs are formed from bone marrow precursors when myelopoietic processes are interrupted, caused by several illnesses.

GM-CSF) and IL6, which promote development of MDSCs that have immune suppressive function in vivo. Other cytokines, including IL10, IL1, VEGF, and PGE2 have been associated with the formation and regulation of MDSCs. GM-CSF promotes synthesis of MDSCs from bone marrow, and the transcription factor c/EBP regulates development of MDSCs in bone marrow and in tumors. STAT3 also promotes development of MDSCs, whereas IRF8 could counteract MDSC-inducing signals.[11]

MDSCs migrate as immature cells from the

fatty acid oxidation). Tumor-infiltrating MDSCs also secrete exosomes
that can inhibit the anti-tumor immune response.

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 tumors secrete a variety of

IL-1 have been implicated in the development and regulation of MDSC.[2][13] The myeloid-differentiation cytokine GM-CSF is a key factor in MDSC production from bone marrow,[14][unreliable medical source?] 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.[14][15] This differentiation process is accelerated upon tumor infiltration and possibly driven by the hypoxic tumor microenvironment.

Phenotype

Natural killer cells

The depletion of MDSCs from mice with liver cancer significantly increases natural killer (NK) cell cytotoxicity, NKG2D expression, and IFNg (IFNg) production and induces NK cell energy.[16] MDSC depletion restored the function of impaired hepatic NK cells. An MDSC derived from chronic inflammation caused T and NK-cell dysfunction along with downregulation of the TCR z chain (CD247). The immunosuppressive milieu directly affects CD247, which is crucial in initiating immune responses. MDSCs, acting through membrane-bound TGF-b1, inhibit NK cells in tumor-bearing hosts due to the activity of TGF-b1 on MDSCs. Therefore, MDSCs constitutively suppress hepatic NK cells in tumor-bearing hosts through TGF-b1 on MDSCs.[17]

B cells

A number of studies have reported MDSC regulation of B-cell responses to activators and mitogens that are not MHC-regulated, as well as antigen-specific T cell responses. An infection with the LP-BM5 retrovirus can cause acquired immune deficiency in mice, which causes highly immunosuppressive CD11bCGr-1CLy6CC MDSCs. These cells suppress T and B cells by signaling via nitric oxide (NO).[18]

Dendritic cells

Immune responses against tumors and infections are regulated by myeloid-derived suppressor cells and dendritic cells (DCs). The combination of LPS and IFNg treatment of bone marrow-derived MDSCs limits DC formation and improves MDSC suppressive action. MDSCs have been shown to reduce the effectiveness of DC vaccinations. MDSC frequency has no effect on DC production or survivability, but it does cause a dose-dependent reduction in DC maturation. High CD14CHLA-DR/low cell frequencies can stifle DC maturation and decrease DC function, both of which are critical for vaccination effectiveness. As a result, the balance between MDSCs and DCs might be crucial in tumor and infection treatment. Thus, the balance between MDSCs and DCs may play an important role in tumor and infection therapy.[19][20]

Activity/function

MDSCs are

tumor maintenance and progression. MDSCs also obstruct therapies that seek to treat cancer through both immunotherapy and other non-immune means.[21]
MDSC activity was originally described as suppressors of
macrophages
. Suppressor activity of MDSC is determined by their ability to inhibit the effector function of
L-arginine. Another important factor influencing the activity of MDSC is oppressive ROS.[2][22]

Effect of MMR vaccination

MDSCs can also play a positive regulatory role. It is stated that

covid-19 induced cytokine inflammation.[citation needed] This vaccination inducement appears to be neither permanent nor chronic.[clarification needed
] Despite MDSC's being immunosuppressive in certain instances, the MMR vaccine itself is immunostimulatory.

MDSC inhibitors

In addition to host-derived factors,

macrophages.[2] In 2015, MDSCs were compared to immunogenic myeloid cells highlighting a group of core signaling pathways that control pro-carcinogenic MDSC functions.[23][unreliable medical source?
] Many of these pathways are known targets of chemotherapy drugs with strong anti-cancer properties.

As of May 2018[update] there are no

FDA approved drugs developed to target MDSCs but experimental INB03 has entered early clinical trials.[24][25]

There is promising evidence for inhibiting Galectin-3 as a therapeutic target to reduce MDSCs.[26][27] 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.[28]

History

The term myeloid-derived suppressor cell originated in a 2007 journal article published in

polymorphonuclear or granulocytic MDSC (PMN-MDSC). M-MDSC are similar to monocytes found in blood, while PMN-MDSC are physically akin to neutrophils.[21]

References

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  28. ^ 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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