Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy
- Ashley J. Knights,
- Jitka Fucikova,
- Anupama Pasam,
- Sandra Koernig,
- Jonathan Cebon
- … show all 5 hide
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Inhibitor of apoptosis proteins (IAPs) are critical in regulating apoptosis resistance in cancer. Antagonists of IAPs, such as LCL161, are in clinical development and show promise as anti-cancer agents for solid and hematological cancers, with preliminary data suggesting they may act as immunomodulators. IAP antagonists hypersensitize tumor cells to TNF-α-mediated apoptosis, an effect that may work in synergy with that of cancer vaccines. This study aimed to further investigate the immunomodulatory properties of LCL161 on human immune subsets. T lymphocytes treated with LCL161 demonstrated significantly enhanced cytokine secretion upon activation, with little effect on CD4 and CD8 T-cell survival or proliferation. LCL161 treatment of peripheral blood mononuclear cells significantly enhanced priming of naïve T cells with synthetic peptides in vitro. Myeloid dendritic cells underwent phenotypic maturation upon IAP antagonism and demonstrated a reduced capacity to cross-present a tumor antigen-based vaccine. These effects are potentially mediated through an observed activation of the canonical and non-canonical NF-κB pathways, following IAP antagonism with a resulting upregulation of anti-apoptotic molecules. In conclusion, this study demonstrated the immunomodulatory properties of antagonists at physiologically relevant concentrations and indicates their combination with immunotherapy requires further investigation.
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- Title
- Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy
- Journal
-
Cancer Immunology, Immunotherapy
Volume 62, Issue 2 , pp 321-335
- Cover Date
- 2013-02-01
- DOI
- 10.1007/s00262-012-1342-1
- Print ISSN
- 0340-7004
- Online ISSN
- 1432-0851
- Publisher
- Springer-Verlag
- Additional Links
- Topics
- Keywords
-
- IAP antagonist
- SMAC mimetic
- Immunomodulatory
- Dendritic cell
- Cross-presentation
- Industry Sectors
- Authors
-
- Ashley J. Knights (1) (2)
- Jitka Fucikova (3)
- Anupama Pasam (1)
- Sandra Koernig (4)
- Jonathan Cebon (1)
- Author Affiliations
-
- 1. Ludwig Institute for Cancer Research Melbourne, Austin Branch, Austin Hospital, 145-163 Studley Road, Heidelberg, VIC, 3084, Australia
- 2. Cellestis Ltd., 1341 Dandenong Rd, Chadstone, VIC, 3148, Australia
- 3. Institute of Immunology, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic
- 4. CSL Limited, 45 Poplar Road Parkville, Melbourne, VIC, 3052, Australia