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).

Contents

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 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. [9] [10] Cancer patients' growing tumors produce cytokines and other substances that affect MDSC development. Tumor cell lines overexpress colony-stimulating factors (G-CSF and 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 bone marrow to peripheral tissues (or tumors), where they differentiate into mature macrophages, dendritic cells, and neutrophils without suppressive phenotypes under homeostatic conditions, but become polarized when exposed to pro-inflammatory compounds, chemokines, and cytokines. In the tumor microenvironment, they suppress the anti-tumor immune response. The presence of MDSCs has been associated with progression of colon cancer, tumor angiogenesis, and metastases. In addition to producing NO and ROS, MDSCs secrete immune-regulatory cytokines such as TNF, TGFB, and IL10. There are subpopulations of MDSC that have some common suppressive characteristics but also have their own unique features; different subpopulations can be found in different areas of the same tissue or tumor. [12] Tumor-infiltrating MDSCs develop in response to environmental factors, upregulating CD38 (which removes NAD from the environment and is necessary for mitochondrial biosynthesis), PDL-1 (an immune checkpoint protein) and LOX1 (promotes fatty acid consumption and fatty acid oxidation). Tumor-infiltrating MDSCs also secrete exosomes that can inhibit the anti-tumor immune response.

Immature Myeloid Cells in Formation of MDSCs

Myeloid-derived suppressor cells (MDSCs) are a recently discovered bone-marrow-derived cell type. They have characteristic of immature stem cells with immunomodulatory properties. In fact, they are used in research to develop therapeutic strategies against both autoimmune diseases and exacerbate inflammation, which has especial interest in the central nervous system). The main inconvenient of MDSCs is that they are only formed during inflammatory conditions, thus being commonly gathered from diseased subjects. [13] [14] [15]

However, a recent research of the University of Salamanca has demonstrated that immature myeloid cells (IMCs), the precursosrs of MDSCs, have also potential immunosuppressive activity under pathological conditions. [16] IMCs can be directly gathered from healthy bone marrow, which is a more clinically feasible source. Then, IMCs under pathological conditions behave as MDSCs exerting immunomodulation. In this sense, IMCs can be directly used thus avoiding their gathering from diseased subjects. [17]

In addition, IMCs are promising adjuvants when performing neurosurgery. They application in an intracranial surgery almost completely prevented the impairments caused by this procedure in mice, probably by the modulation of the inflammatory patterns. [18] In this sense, IMCs have a direct pre-clinical application to minimize the secondary effects inherent to every single intracranial surgery, especially in a diseased environment.

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 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 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] [19] The myeloid-differentiation cytokine GM-CSF is a key factor in MDSC production from bone marrow, [20] [ 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. [20] [21] 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. [22] 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. [23]

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). [24]

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. [25] [26]

Activity/function

MDSCs are immune suppressive and play a role in tumor maintenance and progression. MDSCs also obstruct therapies that seek to treat cancer through both immunotherapy and other non-immune means. [27] 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 by 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] [28]

Effect of MMR vaccination

MDSCs can also play a positive regulatory role. It is stated that MMR vaccine stimulates MDSC populations in people taking the vaccine, inhibiting septic inflammation and mortality that is broadly applicable not only to measles, mumps, and rubella, but extends to 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, 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. [29] [ unreliable medical source? ] 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. [30] [31]

There is promising evidence for inhibiting Galectin-3 as a therapeutic target to reduce MDSCs. [32] [33] 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. [34]

History

The term myeloid-derived suppressor cell originated in a 2007 journal article published in Cancer Research by Gabrilovich et al. Publications in 2008 established that there are two subpopulations of MDSC: mononuclear MDSC (M-MDSC) and polymorphonuclear or granulocytic MDSC (PMN-MDSC). M-MDSC are similar to monocytes found in blood, while PMN-MDSC are physically akin to neutrophils. [27]

Related Research Articles

<span class="mw-page-title-main">Haematopoiesis</span> Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">Interleukin 3</span> Protein-coding gene in the species Homo sapiens

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: after removal of the signal peptide sequence, the mature protein contains 133 amino acids in its polypeptide chain. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

<span class="mw-page-title-main">Granulopoiesis</span> Formation of granulocyte cells in the bone marrow

Granulopoiesis is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. Granulopoiesis takes place in the bone marrow. It leads to the production of three types of mature granulocytes: neutrophils, eosinophils and basophils.

<span class="mw-page-title-main">Interleukin 30</span> Protein-coding gene in the species Homo sapiens

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

<span class="mw-page-title-main">Acute monocytic leukemia</span> Medical condition

Acute monocytic leukemia is a type of acute myeloid leukemia. In AML-M5 >80% of the leukemic cells are of monocytic lineage. This cancer is characterized by a dominance of monocytes in the bone marrow. There is an overproduction of monocytes that the body does not need in the periphery. These overproduced monocytes interfere with normal immune cell production which causes many health complications for the affected individual.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Chemoimmunotherapy is chemotherapy combined with immunotherapy. Chemotherapy uses different drugs to kill or slow the growth of cancer cells; immunotherapy uses treatments to stimulate or restore the ability of the immune system to fight cancer. A common chemoimmunotherapy regimen is CHOP combined with rituximab (CHOP-R) for B-cell non-Hodgkin lymphomas.

<span class="mw-page-title-main">Colony stimulating factor 1 receptor</span> Protein found in humans

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

<span class="mw-page-title-main">NT5E</span> Enzyme converting AMP to adenosine

5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73, is an enzyme that in humans is encoded by the NT5E gene. CD73 commonly serves to convert AMP to adenosine.

<span class="mw-page-title-main">TREM1</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 (TREM1) is an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene. TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.

<span class="mw-page-title-main">CD200</span> Protein found in humans

OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. In humans, the CD200 gene is located on chromosome 3 in proximity to genes encoding the other B7 proteins CD80/CD86. In mice, the CD200 gene is located on chromosome 16.

<span class="mw-page-title-main">IKZF2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein Helios is a protein that in humans is encoded by the IKZF2 gene. This protein is a member of Ikaros family of transcription factors.

Bone-marrow-derived macrophage (BMDM) refers to macrophage cells that are generated in a research laboratory from mammalian bone marrow cells. BMDMs can differentiate into mature macrophages in the presence of growth factors and other signaling molecules. Undifferentiated bone marrow cells are cultured in the presence of macrophage colony-stimulating factor. M-CSF is a cytokine and growth factor that is responsible for the proliferation and commitment of myeloid progenitors into monocytes. Macrophages have a wide variety of functions in the body including phagocytosis of foreign invaders and other cellular debris, releasing cytokines to trigger immune responses, and antigen presentation. BMDMs provide a large homogenous population of macrophages that play an increasingly important role in making macrophage-related research possible and financially feasible.

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

Dmitry Gabrilovich is currently a Chief Scientist, Cancer Immunology at AstraZeneca in Gaithersburg, MD, USA. His research is focused on methods by which tumors are able to suppress the immune system and how to develop new immune therapies to combat this ability. Gabrilovich described the defective ability of dendritic cells in induce immune responses in cancer, and was one of the discoverers of myeloid-derived suppressor cells (MDSC). The Gabrilovich lab focuses on immature myeloid cell biology and its relation to cancer. MDSC have been linked to a number of signaling pathways associated with cancer, including NF-κB, Jak-STAT, Notch, Wnt, and Rb, among others. His research has found that tumor cells can go through a mechanism that produces a free radical peroxynitrite, causing them to become resistant to certain types of cancer immunotherapy. His research has also focused on monocytic-myeloid derived suppressor cells and polymorphonuclear-myeloid derived suppressor cells and what impact they might have on cancer therapy, since myeloid derived suppressor cells negatively regulate anti-tumor activity. His group described methods of targeting suppressive myeloid cell. In 2019 he was awarded title of Research Professor by American Cancer Society. Prior to joining AstraZeneca, Gabrilovich was a researcher and Christopher M. Davis professor at The Wistar Institute in Philadelphia. Prior to joining The Wistar Institute, Gabrilovich was a senior member at the Moffitt Cancer Center in Tampa.

A pre-metastatic niche is an environment in a secondary organ that can be conducive to the metastasis of a primary tumor. Such a niche provides favorable conditions for growth, and eventual metastasis, in an otherwise foreign and hostile environment for the primary tumor cells. This concept demonstrated the fundamental role of the microenvironment in regulating tumor growth and metastasis. The discovery of the pre-metastatic niche has fostered new research regarding the potential treatment of metastases, including targeting myeloid derived suppressor cells, and stromal cell plasticity including fibroblasts and pericytes and perivascular smooth muscle cells and (attempts to stop the flow of vesicles from primary tumors to pre-metastatic niches in secondary organs and different combinations of microenvironment targeted therapies.

The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.

References

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  30. ↑ INmune Bio Initiates Phase I Clinical Trial Of INB03 May 2018
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