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