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Review
. 2015 Feb 3;4(1):e954829.
doi: 10.4161/21624011.2014.954829. eCollection 2015 Jan.

Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy

Oana Draghiciu  1 , Joyce Lubbers  1 , Hans W Nijman  2 , Toos Daemen  1
Affiliations
Review

Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy

Oana Draghiciu et al. Oncoimmunology. .

Abstract

Myeloid-derived suppressor cells (MDSCs) contribute to tumor-mediated immune escape and negatively correlate with overall survival of cancer patients. Nowadays, a variety of methods to target MDSCs are being investigated. Based on the intervention stage of MDSCs, namely development, expansion and activation, function and turnover, these methods can be divided into: (I) prevention or differentiation to mature cells, (II) blockade of MDSC expansion and activation, (III) inhibition of MDSC suppressive activity or (IV) depletion of intratumoral MDSCs. This review describes effective mono- or multimodal-therapies that target MDSCs for the benefit of cancer treatment.

Keywords: 5-FU, 5-fluorouracil; 5-Fluorouracil; ADAM17, metalloproteinase domain-containing protein 17; APCs, antigen presenting cells; ARG1, arginase-1; ATRA, all-trans retinoic acid; CCL2, chemokine (C-C motif) ligand 2; CD62L, L-selectin; CDDO-Me, bardoxolone methyl; COX2, cyclooxygenase 2; CTLs, cytotoxic T lymphocytes; CXCL12, chemokine (C-X-C motif) ligand 12; CXCL15, chemokine (C-X-C motif) ligand 15; DCs, dendritic cells; ERK1/2, extracellular signal-regulated kinases; Flt3, Fms-like tyrosine kinase 3; FoxP3, forkhead box P3; GITR, anti-glucocorticoid tumor necrosis factor receptor; GM-CSF/CSF2, granulocyte monocyte colony stimulating factor; GSH, glutathione; HIF-1α, hypoxia inducible factor 1α; HLA, human leukocyte antigen; HNSCC, head and neck squamous cell carcinoma; HPV-16, human papillomavirus 16; HSCs, hematopoietic stem cells; ICT, 3, 5, 7-trihydroxy-4′-emthoxy-8-(3-hydroxy-3-methylbutyl)-flavone; IFNγ, interferon γ; IL-10, interleukin 10; IL-13, interleukin 13; IL-1β, interleukin 1 β; IL-4, interleukin 4; IL-6, interleukin 6; IMCs, immature myeloid cells; JAK2, Janus kinase 2; MDSCs, myeloid-derived suppressor cells; MMPs, metalloproteinases (e.g., MMP9); Myd88, myeloid differentiation primary response protein 88; NAC, N-acetyl cysteine; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase NK cells, natural killer cells; NO, nitric oxide; NOHA, N-hydroxy-L-Arginine; NSAID, nonsteroidal anti-inflammatory drugs; ODN, oligodeoxynucleotides; PDE-5, phosphodiesterase type 5; PGE2, prostaglandin E2; RNS, reactive nitrogen species; ROS, reactive oxygen species; SCF, stem cell factor; STAT3, signal transducer and activator of transcription 3; TAMs, tumor-associated macrophages; TCR, T cell receptor; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α; Tregs, regulatory T cells; VEGFR, vascular endothelial growth factor receptor; WA, withaferin A; WRE, Withaferin somnifera; all-trans retinoic acid; bisphosphonates; c-kit, Mast/stem cell growth factor receptor; gemcitabine; iNOS2, inducible nitric oxid synthase 2; immune suppressive mechanisms; mRCC, metastatic renal cell carcinoma; myeloid-derived suppressor cells; sunitinib therapeutic vaccination.

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Figures

Figure 1.
Figure 1.
Mechanisms used by MDSCs to decrease antitumor immunity and contribute to tumor immune escape. Under normal circumstances, hematopoietic stem cells (HSCs) located in the bone marrow give rise to immature myeloid cells (IMCs), which differentiate into mature macrophages, dendritic cells (DCs) or granulocytes. In the context of cancer, the tumor microenvironment releases mediators that signal development of IMCs to myeloid-derived suppressor cells (MDSCs) and chemokines that signal MDSC migration to tumors. Immunosuppressive intratumoral MDSCs can: (i) block migration of naïve CD62L+ (L-selectin) T cells to lymphoid organs and subsequent formation of effector T cells; (ii) release factors that stimulate regulatory T cell (Treg) conversion and expansion; (iii) induce intracellular pathways that promote self-expansion; (iv) produce high levels of arginase 1 (ARG-1) that depletes T cells of L-arginine, inducing cell cycle arrest; (v) stimulate production of reactive oxygen and nitrogen species (ROS, RNS) that decrease T cell receptor (TCR) functionality; (vi) nitrate / nitrosylate CD8 and chemokine C-C or C-X-C motif ligands and receptors that contribute to MDSC and, respectively, T cell migration. TNFα, tumor necrosis factor α; TGFβ, transforming growth factor β; IL1β, interleukin 1 β; IL6/10, interleukin 6/10; GM-CSF, granulocyte macrophage colony stimulating factor; SCF, stem cell factor; Flt3, Fms-like tyrosine kinase 3; ARG1, arginase 1; iNOS, inducible nitric oxide synthase; NO, nitric oxide; S100A8 and S100A9, S100 calcium binding proteins; ADAM17,ADAM disintegrin and metallopeptidase domain 17; STAT, signal transducer and activation of transcription; HIF-1α, hypoxia inducible factor 1α; Myd88, myeloid differentiation primary response protein 88; proto-oncogene c-kit, SCF receptor; VEGFR, vascular endothelial growth factor receptor.
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