Invited review articleMyeloid derived suppressor cells and their role in tolerance induction in cancer
Introduction
Several clinical trials for cancer immunotherapy reveal that cancer vaccination therapies can strengthen the immune system against tumors, but their clinical benefits to induce complete tumor regression are still limited [1], [2]. This discrepancy is, at least in part, due to immunosuppressive cells in the tumor microenvironment. Myeloid derived suppressor cells (MDSCs) are one of the key suppressor cells that regulate anti-tumor immune responses in conjunction with regulatory T cells (Tregs) in tumor-bearing hosts.
MDSCs were originally described as a population of CD11b+Gr1+ cells that accumulate in blood and lymphoid organs of tumor-bearing mice [3], [4]. Currently, MDSCs have been reported to comprise a group of heterogeneous immature myeloid cells, which have suppressive biological activities as a common denominator. MDSCs regulate both acquired and innate immunity by direct or indirect pathways. To exert their immunosuppressive function in tumor-bearing hosts, MDSCs are (i) required to expand in lymphoid organs and (ii) are subsequently recruited to the tumor site [3], [5]. There are several factors (e.g. tumor-associated inflammation, angiogenetic factors, chemoattractant fantoes) that orchestrate the expansion and recruitment of MDSCs. This expansion of MDSC is associated with a poor prognosis in tumor-bearing hosts. The activation of MDSCs in tumors upregulates the expression of inducible nitric oxide synthase (iNOS), arginase 1 (ARG 1), and increases the production of nitric oxide (NO) and reactive oxygen species (ROS). Moreover, classical immunosuppressive cytokines such as IL-10 or TGF-β are also secreted. By these means, MDSCs suppress the anti-tumor immune response in the tumor microenvironment directly. Moreover, not only direct effects on effector immune cells are apparent, as MDSCs are involved in the induction of Tregs. These results clearly suggest that the suppression of MDSC-inducible factors or Tregs, respectively, may be beneficial for anti-cancer therapy. In this review, we discuss the definition and suppressive mechanisms of MDSCs, as well as their biological activities in tumor-bearing hosts to assess potential therapeutic strategies (Fig. 1, Table 1).
Section snippets
The definition of MDSCs
MDSCs comprise a phenotypically heterogeneous population of cells, which can be found in tumor-bearing mice and in patients with cancer. In mice, MDSCs were originally described as a population of CD11b+ Gr1+ cells that accumulate in the blood and lymphoid organs during tumor growth [3], [4]. The Gr1 antigen includes the macrophage and neutrophil marker Ly6C and Ly6G, whereas CD11b is characteristic for macrophages. Movahedi et al. divided MDSCs into CD11b+Ly6G+ and CD11b+Ly6C+ subpopulations
Expansion and recruitment of MDSCs
To assess the immunosuppressive function of MDSCs in tumor models, it is important to investigate their systemic expansion, recruitment to the tumor site and enhancement of the suppressive function. In this section, we discuss the expansion and recruitment of MDSCs that is related to tumor-associated inflammation, angiogenic factors and other chemoattractants.
Mechanisms of suppressive activities of MDSCs
To exert their suppressive activity, MDSCs must be activated. Indeed, there are several factors reported, which stimulate MDSCs to turn their suppressive function on. IL-4, IL-13, IFN-γ, IL-1β and TGF-β are known to activate several different pathways in MDSCs that involve STAT6, STAT1 and nuclear factor-κB (NF-κB).
STAT1, STAT3 and STAT6 have been described to have distinct roles in macrophage polarization [4]. While STAT3 regulates the expansion of MDSCs through the S100A9/N-glycan pathway [21]
MDSC as a therapeutic target
After expansion in the periphery, MDSCs migrate to tumor sites and become activated to express arginase 1 and iNOS. Indeed, the levels of NO and arginase 1 in tumor sites are much higher as compared to the periphery [4]. Moreover, these activated MDSCs produce immunosuppressive cytokines such as IL-10 and TGF-β to promote a systemic immunosuppression against tumors [45]. MDSCs even secrete IFN-γ. Instead of being directly immunosuppressive, IFN-γ enhances the production of TGF-β and IL-10 by
Concluding remarks
MDSCs are a group of heterogeneous immature myeloid cells that have common biological activities, i.e. the suppression of immune responses. Although several studies suggested that high numbers of MDSCs in tumor-bearing individuals is associated with poor prognosis, further investigations will be required to quantify the impact of MSDC on survival in different cancers. Clinical studies for targeting MDSCs are limited to only a few tumor types (e.g. renal cell carcinoma, colon caner, melanoma)
Acknowledgement
This study was supported by Alexander von Humboldt foundation, the Tumor center Heidelberg/Mannheim and the Helmholtz Alliance against Cancer.
Dr. Taku Fujimura graduated from Tohoku University, graduate school of medicine and received his MD degree in 1998. He received his PhD in dermatology at Tohoku University in 2004. From 2004 to 2007, he worked as an assistant professor in Department of Dermatology, Tohoku University graduate school of medicine. Since 2007, he has studied tumor immunology under the supervision of Professor Alexander H Enk and Professor Karsten Mahnke at Department of Dermatology, University of Heidelberg as a
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Dr. Taku Fujimura graduated from Tohoku University, graduate school of medicine and received his MD degree in 1998. He received his PhD in dermatology at Tohoku University in 2004. From 2004 to 2007, he worked as an assistant professor in Department of Dermatology, Tohoku University graduate school of medicine. Since 2007, he has studied tumor immunology under the supervision of Professor Alexander H Enk and Professor Karsten Mahnke at Department of Dermatology, University of Heidelberg as a Humbolt Foundation fellow where he investigated the crosstalk of myeloid derived suppressor cells and regulatory T cells during melanoma growth. His research interests include tumor immunology and cutaneous immunology.