Dendritic Cells in Myelodysplastic Syndromes

From Pathogenesis to Immunotherapy

Nathalie Kerkhoff; Hetty J Bontkes; Theresia M Westers; Tanja D de Gruijl; Shahram Kordasti; Arjan A van de Loosdrecht

Disclosures

Immunotherapy. 2013;5(6):621-637. 

In This Article

DCs in MDS

In diverse cancer types, including myeloid malignancies, it has been revealed that DCs are affected and may contribute to disturbed immune responses.[84–88] FISH and immunophenotypic analysis have even confirmed the clonal involvement of DCs.[89] Until now, several studies have been published on the frequencies and functional capacities of DCs derived from MDS patients. Matteo Rigolin et al. showed that DCs obtained from peripheral blood after in vitro culture are reduced in number in MDS patients compared with healthy donors.[89] Moreover, the expression of accessory molecules, such as CD54, CD80 and CD86, is lower on MDS DCs and their capability to stimulate T cells in a MLR is reduced. Furthermore, the endocytic ability is impaired in MDS DCs.[89] Other groups confirmed decreased frequencies and impaired function of circulating plasmacytoid and myeloid DCs in MDS.[90,91] The DCs exhibit diminished maturation and poor induction of T-cell proliferation. In addition, immature DCs from MDS patients showed an altered cytokine-secretion profile after stimulation with lipopolysaccharide/IFN-γ; they secrete less IL-12p70, whereas the production of IL-10 is increased. In healthy subjects, DCs turn from a cytokine-secreting profile into an antigen-presenting mode after maturation induction, while MDS DCs continue to secrete cytokines (IL-12, TNF-α and IL-10).[92]

In most studies, DCs were generated from CD14+ monocytes (monocyte-derived DCs [MoDCs]) from peripheral blood or from bone marrow CD34+ progenitors. The latter procedure was less effective in MDS patients.[91,93] Of note, MoDCs function and behave differently than 'naturally occurring' DCs.[94]

Recently, Saft et al. reported for the first time DC frequencies in the bone marrow of MDS patients.[95] Both pDCs and CD11c+ myeloid DCs are decreased in MDS patients and lower numbers of DCs are associated with a higher risk profile. In this study, the myeloid DC subset was not divided into the two subpopulations, namely CD1c+ DCs and CD141+ DCs.[95]

In summary, DCs are widely affected in MDS with respect to frequencies of different subsets, maturation, cytokine secretion and induction of T-cell proliferation (Figure 2A). As mentioned above, it has been shown that the DC compartment can also be clonally involved in MDS, which may clarify disturbed functionality of these cells. Whether this involvement contributes to the pathogenesis of the disease itself or whether it is a result of different immunological processes (or both) remains, as yet, unclear. It can be hypothesized that in myeloid diseases, such as MDS, defects in cells that play a crucial role in orchestrating immune responses are highly relevant in the pathophysiology of the disease.

Figure 2.

Dendric cells in myelodysplastic syndromes. (A) Different components of DC function are impaired in MDS. MDS DCs take up antigens less efficiently. They also display impaired maturation and an altered cytokine-secretion profile. Rather than producing proinflammatory cytokines, they secrete high amounts of anti-inflammatory cytokines (e.g., IL-10). The T-cell-stimulating capacity is also diminished, resulting in less T-cell proliferation. To restore DC function in MDS patients, different immunotherapeutic options are available. The hypomethylating agent azacitidine and immunomodulating drug lenalidomide both exert modulating effects on DC function. (B) Additionally, other strategies, such as DC vaccination and in vivo DC targeting, could modify DC function. In the context of DC vaccination, autologous MDS DCs or allogeneic DCs can be used to load them ex vivo with MDS-specific antigens. These DCs will then be given back to the patient to induce MDS-specific CTL responses. As a future perspective, in vivo DC targeting can be hypothetically achieved via antigens fused with an antibody that specifically recognizes a DC receptor. This could result in inflammatory or anti-inflammatory responses depending on the desired outcome in different stages of disease. In low-risk MDS, a restoration of the balance between immunity and immune suppression can be the focus of this strategy, whereas in high-risk disease, the tolerogenic environment can be overcome by inducing a MDS-specific CTL response.
CLR: C-type lectin receptor; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; MDS: Myelodysplastic syndrome; PAMP: Pathogen-associated molecular pattern; TAA: Tumor-associated antigen; TLR: Toll-like receptor.

Further investigation of DC subsets, including the subdivision of myeloid DCs into CD1c+ and CD141+ DCs in peripheral blood, as well as in the bone marrow of MDS patients, is needed to confirm that naturally occurring DCs are also quantitatively and functionally affected and contribute to the dysregulation of the immune system and the ability of the dysplastic clone to escape from immune recognition. Differential DC dysregulation within various risk groups may hypothetically contribute to inflammatory reactions in low-risk MDS, whereas in high-risk disease, a tolerogenic environment might be supported.

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