Myeloid-derived Suppressor Cell

Definition

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), to which dendritic cells, macrophages and neutrophils also belong. MDSCs strongly expand in pathological situations such as chronic infections and cancer, as a result of an altered hematopoiesis. Thus, it is yet unclear whether MDSCs represent a group of immature myeloid cell types that have stopped their differentiation towards DCs, macrophages or granulocytes, or if they represent a myeloid lineage apart. MDSCs are however discriminated from other myeloid cell types in which they possess strong immunosuppressive activities rather than immunostimulatory properties. Similarly to other myeloid cells, MDSCs interact with other immune cell types including T cells (the effector immune cells that kill pathogens, infected and cancer cells), dendritic cells, macrophages and NK cells to regulate their functions. Their mechanisms of action are beginning to be understood although they are still under heated debate and close examination by the scientific community. Nevertheless, clinical and experimental evidence has shown that cancer tissues with high infiltration of MDSC are associated with poor patient prognosis and resistance to therapies.[1][2][3][4]

Phenotype

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.

Human MDSCs are less characterized, and they are generally defined as myeloid cells expressing CD33, CD11b 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 no international consensus on how human subsets of MDSC should be defined.[5]

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

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.[1][6] The myeloid-differentiation cytokine GM-CSF is a key factor in MDSC production from bone marrow,[7] 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.

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.[7][8] This differentiation process is accelerated upon tumour infiltration and possibly driven by the hypoxic tumor microenvironment.

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.[1][9]

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.[1] Recently, MDSCs were compared to immunogenic myeloid cells highlighting a group of core signaling pathways that control pro-carcinogenic MDSC functions.[10] Many of these pathways are known targets of chemotherapy drugs with strong anti-cancer properties.

The rapidly accumulating new information has shed new light on molecular pathways and diversity of MDSC. As usual, new evidence raises new questions or revisits old questions.[1]

References

  1. 1 2 3 4 5 Mantovani, Alberto (1 December 2010). "The growing diversity and spectrum of action of myeloid-derived suppressor cells". European Journal of Immunology 40 (12): 3317–3320. doi:10.1002/eji.201041170.
  2. ↑ Allavena, P.; Mantovani, A. (1 February 2012). "Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment". Clinical & Experimental Immunology 167 (2): 195–205. doi:10.1111/j.1365-2249.2011.04515.x.
  3. ↑ Galdiero, Maria Rosaria; Bonavita, Eduardo; Barajon, Isabella; Garlanda, Cecilia; Mantovani, Alberto; Jaillon, Sébastien (1 November 2013). "Tumor associated macrophages and neutrophils in cancer". Immunobiology 218 (11): 1402–1410. doi:10.1016/j.imbio.2013.06.003.
  4. ↑ Gabrilovich, Dmitry I.; Ostrand-Rosenberg, Suzanne; Bronte, Vincenzo (21 March 2012). "Coordinated regulation of myeloid cells by tumours". Nature Reviews Immunology 12 (4): 253–268. doi:10.1038/nri3175.
  5. ↑ Poschke et al, (2012) "On the armament and appearance of human myeloid-derived suppressor cells". Clinical Immunology doi 10.1016/j.clim.2012.06.003
  6. ↑ Gros, A.; Turcotte, S.; Wunderlich, J. R.; Ahmadzadeh, M.; Dudley, M. E.; Rosenberg, S. A. (26 July 2012). "Myeloid Cells Obtained from the Blood but Not from the Tumor Can Suppress T-cell Proliferation in Patients with Melanoma". Clinical Cancer Research 18 (19): 5212–5223. doi:10.1158/1078-0432.CCR-12-1108.
  7. 1 2 Therese Liechtenstein; Perez-Janices, Noemi; Gato, Maria; Caliendo, Fabio; Kochan, Grazyna; Blanco-Luquin, Idoia; Van Der Jeught, Kevin; Arce, Frederick; Guerrero-Setas, David; Fernandez-Irigoyen, Joaquin; Santamaria, Enrique; Karine, Breckpot; Escors, David (15 September 2014). "A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice". Oncotarget 5 (17): 7843–7857. doi:10.18632/oncotarget.2279.
  8. ↑ Youn JI; Kumar V; Collazo M; Nefedova Y; Condamine T; Cheng P; Villagra A; Antonia S; McCaffrey JC; Fishman M; Sarnaik A; Horna P; Sotomayor E; Gabrilovich DI (March 2013). "Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.". Nat Immunol 14 (3): 211–220. doi:10.1038/ni.2526.
  9. ↑ Kusmartsev, S; Nefedova, Y; Yoder, D; Gabrilovich, DI (Jan 15, 2004). "Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.". Journal of immunology (Baltimore, Md. : 1950) 172 (2): 989–99. doi:10.4049/jimmunol.172.2.989. PMID 14707072.
  10. ↑ Gato-Cañas M; Martinez de Morentin X; Blanco-Luquin I; Fernandez-Irigoyen J; Zudaire I; Liechtenstein T; Arasanz H; Lozano T; Casares N; Chaikuad A; Knapp S; Guerrero-Setas D; Escors D; Kochan G; Santamaría E (23 July 2015). "A core of kinase-regulated interactomes defines the neoplastic MDSC lineage.". Oncotarget.
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