Review
Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression

https://doi.org/10.1016/j.semcancer.2012.01.011Get rights and content

Abstract

The tumor microenvironment is a complex milieu of tumor and host cells. Host cells can include tumor-reactive T cells capable of killing tumor cells. However, more frequently the tumor and host components interact to generate a highly immune suppressive environment that frustrates T cell cytotoxicity and promotes tumor progression through a variety of immune and non-immune mechanisms. Myeloid-derived suppressor cells (MDSC) are a major host component contributing to the immune suppressive environment. In addition to their inherent immune suppressive function, MDSC amplify the immune suppressive activity of macrophages and dendritic cells via cross-talk. This article will review the cell–cell interactions used by MDSC to inhibit anti-tumor immunity and promote progression, and the role of inflammation in promoting cross-talk between MDSC and other cells in the tumor microenvironment.

Section snippets

Myeloid-derived suppressor cells (MDSC)

MDSC are immune suppressive immature myeloid cells that are elevated in virtually all patients and experimental mice with malignancies. MDSC include two major subpopulations of cells: monocytic and granulocytic (polymorphonuclear) MDSC, as defined by their expression of plasma membrane markers and their content of immune suppressive molecules. They enhance tumor growth through both non-immune and immune suppressive mechanisms. Their principle non-immune mechanism is the promotion of

Tumor-associated macrophages

In healthy individuals macrophages are key cells that promote host survival by regulating adaptive immunity, promoting wound healing, and eliminating infectious agents (reviewed in [25]). Similar to MDSC, macrophages are a diverse population of myeloid cells and facilitate tumor progression via both immunological and non-immunological mechanisms. They form a continuous spectrum of cells that range in phenotype from M1-like or classically activated macrophages to M2-like or

Dendritic cells

The major function of dendritic cells (DC) is to process and present antigen for the activation of CD4+ and CD8+ T cells. Endocytosis of antigen by immature DC drives DC maturation and the subsequent presentation of antigen to T cells. However, the tumor microenvironment systemically perturbs this process by increasing the accumulation of immature DC and decreasing DC maturation [31]. As a result, DC fail to activate tumor-reactive T cells and/or become tolerogenic. Defective dendritic cell

Bidirectional cross-talk between MDSC and macrophages exacerbates immune suppression

In individuals with tumors, the accumulation and suppressive activity of MDSC and TAMs is initiated by factors produced by tumor cells. Many of these factors act directly on MDSC and TAMs. However, interactions between MDSC and macrophages further exacerbate suppression by these cells by altering cytokine production and expression of cell surface molecules important for cellular function (Fig. 1).

Tumoricidal M1-like macrophages have a phenotype of IL-12hiIL-10lo and are activated by LPS and

Inflammation exacerbates bidirectional cross-talk between MDSC and macrophages

The accumulation of MDSC as well as the immune suppressive mechanisms used by MDSC are exacerbated by chronic inflammation [50], [51], [52], [53], and inflammation also increases cross-talk between MDSC and macrophages (Fig. 2). The effect of inflammation on MDSC–macrophage cross-talk was demonstrated using two approaches to increase the inflammatory milieu. In one approach, tumor cells were transfected with the gene encoding IL-1β so the tumor microenvironment contained heightened levels of

Inflammation increases MDSC–NK cell cross-talk

In addition to their cross-talk with other myeloid cells, MDSC also impact NK cells and reduce their suppressive activity [18], and inflammation increases these effects in a unidirectional fashion [20]. NK cell differentiation is characterized by the expression of CD27 on immature NK cells and increasing expression of CD11b and KLRG-1 as NK cells mature [58]. Inflammation, via IL-1β, decreases the levels of CD27 on immature CD27+ NK cells in the bone marrow, and eliminates CD11b+KLRG-1+ NK

MDSC–macrophage cross-talk reduces inflammation

Within the tumor microenvironment tumor cells and stromal cells, including MDSC and macrophages, generate a pro-inflammatory environment. Different tumor cells produce a variety of pro-inflammatory mediators including prostaglandins, cyclooxygenases, IL-6, TNFα, as well as many other mediators [60]. Although inflammation drives MDSC accumulation and suppressive potency [53], and MDSC themselves produce inflammatory mediators [61], [62], MDSC also reduce inflammation through their production of

MDSC–DC cross-talk contributes to DC dysfunction

In contrast to MDSC–macrophage interactions, there is less information on cross-talk between MDSC and DC. As discussed above, in many cancer patients the numbers of mature DC are reduced and DC function is deficient. Although multiple factors are likely to contribute to DC dysfunction, evidence is accumulating that MDSC–DC cross-talk may at least be partially responsible. In vitro studies in which mouse MDSC were differentiated from c-kit+ bone marrow progenitor cells in the presence of IL-4,

Conclusions

The tumor microenvironment includes diverse host cells that are chemoattracted and induced by tumor-produced factors to generate a highly immune suppressive environment. This review has described some of the host cell cross-talk between MDSC, macrophages, and DC that results in suppressing anti-tumor immunity. Because we are just beginning to understand the complexity of the tumor microenvironment, it is likely there are additional interactions that further promote tumor progression through

Acknowledgements

The authors thank Ms. Lakshmi Gorrepati for performing the initial IL-23 experiments and Jonathan Weiss for suggesting the rapamycin and mTOR experiments. Original studies were supported by NIH RO1CA115880, RO1CA84232 (SOR), and American Cancer Society IRG-97-153-07 (PS). DWB is supported by a pre-doctoral fellowship from the DOD Breast Cancer Program (W81XWH-11-1-0115).

References (70)

  • F. Balkwill et al.

    Smoldering and polarized inflammation in the initiation and promotion of malignant disease

    Cancer Cell

    (2005)
  • V. Schaeffer et al.

    Role of the mTOR pathway in LPS-activated monocytes: influence of hypertonic saline

    J Surg Res

    (2011)
  • B.S. McKenzie et al.

    Understanding the IL-23-IL-17 immune pathway

    Trends Immunol

    (2006)
  • Trial watch: ipilimumab success in melanoma provides boost for cancer immunotherapy. Nat Rev Drug Discov...
  • F.S. Hodi et al.

    Improved survival with ipilimumab in patients with metastatic melanoma

    N Engl J Med

    (2010)
  • J.R. Brahmer et al.

    Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates

    J Clin Oncol

    (2010)
  • A.V. Ezernitchi et al.

    TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs

    J Immunol

    (2006)
  • S. Nagaraj et al.

    Mechanism of T cell tolerance induced by myeloid-derived suppressor cells

    J Immunol

    (2010)
  • A. Mazzoni et al.

    Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism

    J Immunol

    (2002)
  • S. Nagaraj et al.

    Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer

    Nat Med

    (2007)
  • T. Lu et al.

    Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice

    J Clin Invest

    (2011)
  • P.C. Rodriguez et al.

    Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses

    Cancer Res

    (2004)
  • M.K. Srivastava et al.

    Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine

    Cancer Res

    (2010)
  • E.M. Hanson et al.

    Myeloid-derived suppressor cells down-regulate l-selectin expression on CD4+ and CD8+ T cells

    J Immunol

    (2009)
  • B. Molon et al.

    Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

    J Exp Med

    (2011)
  • B. Huang et al.

    Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host

    Cancer Res

    (2006)
  • P.Y. Pan et al.

    Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer

    Cancer Res

    (2010)
  • P. Serafini et al.

    Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells

    Cancer Res

    (2008)
  • H. Li et al.

    Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1

    J Immunol

    (2009)
  • E. Suzuki et al.

    Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity

    Clin Cancer Res

    (2005)
  • M. Elkabets et al.

    IL-1beta regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function

    Eur J Immunol

    (2010)
  • B. Hoechst et al.

    Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor

    Hepatology

    (2009)
  • T.J. Stewart et al.

    Inhibition of early tumor growth requires J alpha 18-positive (natural killer T) cells

    Cancer Res

    (2003)
  • M. Terabe et al.

    A nonclassical non-Valpha14Jalpha18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance

    J Exp Med

    (2005)
  • M. Terabe et al.

    Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence

    J Exp Med

    (2003)
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