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

Conclusion & Future Perspective

The professional APC characteristics of DCs render them as attractive candidates for immune-intervening approaches to eliminate the dysplastic clone in MDS patients. Beside ex vivo generated DC vaccinations as a technique to deliver antigens and induce T-cell immunity, other DC-targeting methods can also be implemented. It can be hypothesized that DC targeting in vivo via antigens fused with an antibody that specifically recognize a DC receptor can induce various immune responses (Figure 2B). As stated above, a different approach of immune-targeted therapies is required in low- versus high-risk MDS. The induction of tolerogenic DCs may dampen the proinflammatory environment and reduce the high apoptotic rate of hematopoietic precursors because of the highly activated immune system in low-risk disease. Antigen delivery via DC receptors without additional maturation stimuli could result in tolerance rather than immunity, which therefore can be of interest in the context of low-risk MDS. Tolerogenic DCs could also be generated with antigen-conjugated anti-DEC-205 (CD205).[163,164] This receptor is involved in antigen phagocytosis and cross-presentation. It is expressed on different APCs, but it shows high expression levels on myeloid DCs.[165] Production of immunosuppressive cytokines, such as IL-10 and TGF-β, is increased by these DCs, which results in the generation of Foxp3+ Tregs. In low-risk MDS, restoration of the balance between immunity and immune suppression should be the main focus of this targeting strategy (Figure 2B).

However, in high-risk patients, immune responses are essential to overcoming the tolerogenic environment created by malignant cells. It has been shown that targeting CLEC9A, which is exclusively expressed by the cross-presenting BDCA3+ subset, enhances specific CD4 and CD8 T-cell proliferative responses.[80,166] In a mouse model, antigen epitopes coupled to a CLEC9A-specific antibody elicit CTL responses and mediate eradication of metastasis, suggesting a relevant role in anticancer therapies (Figure 2B).[167] As mentioned before, DCs in MDS patients can be part of the aberrant clone and, therefore, their function might be impaired and frequencies of properly differentiated DCs can be reduced. Whether this hampers the use of in vivo DC targeting has to be investigated. Combining different (immuno)therapeutic strategies could potentially increase the efficacy of treatment. For instance, in low-risk MDS, where the progenitor cells are highly apoptotic due to high TNF-α, anticytokine therapy can be employed in order to create anti-inflammatory responses. However, in high-risk MDS, immune-specific reactivity is required and therefore agents against immune-inhibiting processes or Treg-converting approaches in combination with hypomethylating drugs, which increase antigen expression in aberrant clones, could provide desired immunological outcomes.[168]

In conclusion, unraveling the involvement of DCs in MDS pathogenesis will provide a better understanding of the immune dysregulation mechanisms that are present in this disease. The phenotypical and functional differences between DC subsets and their role in T-cell polarization and cross-presentation are of utmost importance in the development of new immunotherapeutic agents. Different approaches are required in low-risk versus high-risk MDS. In low-risk disease, it can be hypothesized that anti-inflammatory responses are desired, whereas in high-risk disease, the tolerogenic environment needs to be overcome in order to provoke 'antidysplastic' responses. Therefore, combining conventional regimens with different DC-based therapies forms an interesting method to improve the outcome of MDS patients in different risk groups.

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