Avid Bioservices Inc (CDMO)

[biopharm]

Dmitry Gabrilovich : Peregrine Pharmaceuticals KOL :

Dmitry is the expert on MDSC's and just posting the main MDSC page from Wiki as it was just updated August 5, 2014 and this will be guaranteed to change over the next month or two

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MDSC (myeloid-derived suppressor cells) are a heterogenous population of immune cells from the myeloid lineage, to which dendritic cells, macrophages and neutrophils also belong. These cells possess strong immunosuppressive activities. The word "myeloid" was originated from Greek language ("Myelos" +"eidos"), meaning "bone marrow" or "spinal cord". "Myeloid lineage" is a cluster of different cell types that all originated from bone marrow stem cells. Although bearing a diverged path of development than T cells, which were originated from thyroid, myeloid lineage cells interacts with T cells in many functional mechanisms, some of which, are still under heated debate and close examination in scientific community.

MDSC are usually defined in mouse models as myeloid cells expressing high levels of CD11b and GR1, which exhibit potent T cell inhibitory activities. In human, MDSC are generally defined as expressing high levels of CD33, CD11b. However, it remains to be resolved as there are no international consensus on how human subsets of MDSC should be defined. [1]

Generally speaking, regardless of whether they are from mice or human, MDSC cells' suppressor function lies in their ability to inhibit T cell proliferation and activation. In healthy individuals, immature myeloid cells formed in the bone marrow differentiated 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. Therefore, they have become a key therapeutic target.

Clinical and experimental evidence has shown that cancer tissues with high in?ltration of MDSC are associated with poor patient prognosis and resistance to therapies.[2][3][4][5]

It has been shown that the c/EBPß 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. [2]

Cytokines 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][6]

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][7]

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]

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.[2]
References

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
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.
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.
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.
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.
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.
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. PMID 14707072.

http://en.wikipedia.org/wiki/Myeloid-derived_Suppressor_Cell

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Remember... Dmitry is just now speaking out much more vocally, regarding MDSC's, as in his last presentation.

1st Annual Summit on Practical Applications of Immune and Oncolytic Therapies in Oncology

The role of myeloid-derived suppressor cells as a therapeutic target

.... now the entire presentation you need to watch. Dmitry even gets the crowd laughing a bit at the end : ) though, I like the part leading up to the 8 min mark:

:MDSC as predictors of clinical outcome in cancer:

Melanoma:

* Clinical responders to ipilimumab therapy showed significantly less MDSC as compared to non-responders. MDSC may be used as predictive marker of response

* Frequency of MDSC correlated with disease progression and decreased overall survival.

* ....
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