Elsevier

Human Immunology

Volume 75, Issue 11, November 2014, Pages 1128-1137
Human Immunology

Review
Phenotypes, accumulation, and functions of myeloid-derived suppressor cells and associated treatment strategies in cancer patients

https://doi.org/10.1016/j.humimm.2014.09.025Get rights and content

Abstract

Myeloid-derived suppressor cells (MDSCs) comprise a group of heterogeneous and immature myeloid-derived cells. MDSCs accumulate in the blood, lymphoid organs, spleens and tumor tissues under different pathogenic conditions such as infection, trauma, hematosepsis, and especially oncogenesis. MDSCs can suppress both adaptive and innate immunities through multiple mechanisms. However, most of our knowledge of MDSCs is based on pre-clinical studies. Clinical observations have shown that the number of MDSCs in the peripheral blood of patients is closely related to tumor stage, tumor burden, remote metastasis and prognosis, though inconsistencies in MDSC phenotypes among cancer patients mean that results have been inconclusive, and subsequent research progress has been slow. This review summarizes recent studies that have investigated MDSCs in cancer patients.

Introduction

Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of cells of myeloid origin composed of myeloid progenitor cells, and immature macrophages, granulocytes and dendritic cells. MDSCs accumulate in the peripheral blood, lymphoid organs, spleens and tumor tissues under pathological conditions such as infection, sepsis, trauma, bone marrow transplantation, some autoimmune diseases, and especially cancer. As many as 20–40% of nucleated splenocytes were shown to be MDSCs in several mouse tumor models, compared with the 2–4% seen in normal mice [1]. The numbers of MDSCs in the peripheral blood in cancer patients are positively correlated with tumor burden, clinical stage [2], [3], [4]. The phenotype of MDSCs in mice is CD11b+Gr1+, and MDSCs can be classified as either granulocytic MDSCs (G-MDSCs) (CD11b+Ly6G+Ly6Clow) or monocytic MDSCs (M-MDSCs) (CD11b+Ly6GLy6Chi). Terminally-differentiated G-MDSCs represent 70–80% of MDSCs and generate reactive oxygen species (ROS). M-MDSCs, which account for 20–30% of MDSCs, retain the ability to differentiate into mature dendritic cells and macrophages, and produce reactive nitrogen species [5]. In addition to their suppressive effects on adaptive immune responses, MDSCs have also been reported to suppress innate immune responses, and have demonstrated non-immunological functions, such as the promotion of tumor angiogenesis and metastasis [1]. Most of our knowledge of MDSCs is based on pre-clinical studies. However, despite the plasticity of MDSCs and variations in their phenotypes among different human malignancies, much progress has recently been made in understanding their role in human cancer. This review summarizes and discusses the phenotypes, accumulation mechanisms and functions of MDSCs, their relationship with clinical outcome, and the potential of targeting these cells for therapeutic benefit in cancer patients. This review not only considers MDSCs in human cancer, but also discusses the different subtypes of MDSCs (Fig. 1).

Section snippets

Phenotypes of MDSCs in cancer patients

The presence of MDSCs in cancer patients was first demonstrated almost two decades ago [6]; however, despite criteria for identifying MDSCs in humans are still lacking. Studies in humans are complicated by the phenotypic diversity of MDSCs, leading to controversial results. Initial studies detected an increase in the number of myeloid origin cells in the peripheral blood of patients with squamous cell carcinomas of the head and neck (HNSCC), compared with the numbers in healthy people. These

Mechanisms of MDSC accumulation in cancer patients

It is currently unclear if the apparent diversity of MDSC subsets is associated with different mechanisms of induction and/or accumulation in various cancers, or is attributable to the use of different surface markers by different investigators. Studies have shown that the numbers of MDSCs in the peripheral blood of patients correlate with clinical cancer stage and metastatic tumor burden [2], [4], [13], [22], [23], [24], [25], and surgical removal of tumors resulted in a reduction in MDSCs in

Immunosuppressive mechanisms of MDSCs in cancer patients

Immunosuppression is one of the most important biological characteristics of MDSCs. MDSCs could suppress proliferation and T cell immunological function in patients with different cancers, and could reduce the secretion of IFN-γ and IL-2 by T cells (Table 2) [4], [8], [14], [15], [17], [20], [22], [25], [31], [36], [37]. Data from pre-clinical studies in mouse models showed that MDSCs suppressed T-cell activity mainly by modulating l-arginine metabolism via up-regulation of arginase 1 (Arg1)

Non-immunological functions of MDSCs in cancer patients

Fibrocytes are a novel subset of cancer-induced CD14CD11chiCD123 MDSCs in pediatric sarcoma patients reported by Zhang et al. [19]. They may contribute to tumor progression not only via immune evasion, but also via angiogenesis. Electronically-sorted CD14CD11chiCD123 MDSCs obtained from cancer-bearing subjects induced cell-dose-dependent new vessel development in a standard tube-formation assay, while no such effect was induced by CD14+ monocytes from the same subjects [19]. In patients

Relationship between MDSCs and clinical outcome in cancer patients

Table 2 summarizes the relationship between MDSCs and clinical outcome in cancer patients. The presence of immune suppressive CD34+ MDSCs in GM-CSF-producing HNSCC leads to increased tumor recurrence or metastasis, and is associated with a poor prognosis [9]. Data from untreated patients with diffuse large B-cell lymphoma (DLBCL) showed that bone marrow involvement, international prognostic index (IPI) score and M-MDSCs were the only independent prognostic factors associated with decreased

Clinical treatment strategies targeting MDSCs in cancer patients

Several therapeutic strategies aimed at modulating MDSCs have been applied in tumor-bearing mice. These include strategies that: (1) promote the differentiation of MDSCs into mature, non-suppressive cells (all-trans-retinoic acid, vitamin D); (2) decrease MDSC levels (gemcitabine, 5-flourouracil); and (3) functionally inhibit MDSCs (phosphodiesterase-5 inhibitors, COX2 inhibitors). Although there are many methods targeting MDSCs in tumor-bearing mice, not all these can be safely applied in

Problems and perspectives

Results from tumor-bearing mice and clinical trials have revealed the plasticity of MDSCs. One of the main challenges to research on MDSCs is their heterogeneity and the absence of a universal marker. The availability of a wide spectrum of markers to describe different MDSC subsets in humans has limited the success of MDSC targeting in clinical situations and led to a lack of consensus in the literature. In addition, limitations in acquiring tumor tissues from cancer patients mean that most

Acknowledgement

This work was supported by Grants from the National Natural Science Foundation of China (81101551).

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