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Updated: May 31, 2026
Generation of Monocyte-Derived Dendritic Cells with Differing Sialylated Phenotypes
Published on: October 20, 2023
SMAC mimetic BV6 induces cell death in monocytes and maturation of monocyte-derived dendritic cells
Nicole Müller-Sienerth1, Lena Dietz, Philipp Holtz
1Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
Background:
Compounds mimicking the inhibitory effect of SMAC/DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NFκB system and TNF signaling. In view of the overwhelming importance of the NFκB transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells.
Principal Findings:
BV6 induced apoptotic and necrotic cell death in monocytes while T-cells, dendritic cells and macrophages were largely protected against BV6-induced cell death. In immature dendritic cells BV6 treatment resulted in moderate activation of the classical NFκB pathway, but it also diminished the stronger NFκB-inducing effect of TNF and CD40L. Despite its inhibitory effect on TNF- and CD40L signaling, BV6 was able to trigger maturation of immature DCs as indicated by upregulation of CD83, CD86 and IL12.
Significance:
The demonstrated effects of SMAC mimetics on immune cells may complicate the development of tumor therapeutic concepts based on these compounds but also arise the possibility to exploit them for the development of immune stimulatory therapies.
Insights
SMAC mimetic BV6 induces cell death in monocytes but activates dendritic cell maturation. These findings suggest potential applications for BV6 in immune-based cancer therapies, despite complicating tumor-sensitizing strategies.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Therapy
Background:
- Developed SMAC/DIABLO mimetics to inhibit XIAP and sensitize resistant tumor cells to apoptosis.
- SMAC mimetics exhibit complex effects on NFκB and TNF signaling pathways.
- Investigated the impact of SMAC mimetic BV6 on immune cells due to the critical role of NFκB in immunity.
Purpose of the Study:
- To analyze the effects of the SMAC mimetic BV6 on various immune cell types.
- To understand the intricate interactions between SMAC mimetics, NFκB, and TNF signaling in immune cells.
Main Methods:
- Treatment of monocytes, T-cells, dendritic cells, and macrophages with BV6.
- Assessment of cell death induction (apoptosis and necrosis).
- Analysis of NFκB pathway activation and response to TNF and CD40L.
- Evaluation of dendritic cell maturation markers (CD83, CD86, IL12).
Main Results:
- BV6 induced cell death in monocytes but protected T-cells, dendritic cells, and macrophages.
- BV6 moderately activated the NFκB pathway in immature dendritic cells.
- BV6 inhibited TNF and CD40L signaling but promoted dendritic cell maturation.
Conclusions:
- SMAC mimetics like BV6 have dual effects on immune cells, potentially complicating anti-cancer therapy development.
- The immune-modulatory effects of BV6 offer possibilities for developing novel immune-stimulatory therapies.
- Further research is needed to harness these effects for therapeutic benefit.
