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Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy

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Abstract

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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Acknowledgments

The contents of the published material are solely the responsibility of the Administering Institution, a Participating Institution or individual authors and do not reflect the views of NHMRC. LCL161 and LBW242 were provided by Dale Porter, Novartis Institutes for Biomedical Research, USA. NY-ESO-1/ISCOMATRIX was kindly provided by CSL Ltd. Melbourne. Buffy Coats were provided by the Red Cross Blood Service, Melbourne. We thank Rodica Stan for her helpful revision of the manuscript. Operational Infrastructure Support Program Funding of the Victorian Government and NHMRC Independent Research Institutes Infrastructure Support Scheme. JC is an NHMRC Practitioner Fellow. JF was supported by grant IGA NT12402-5 from the Ministry of Health, Czech Republic.

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The authors declare that they have no conflict of interest.

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Author notes

  1. Ashley J. Knights

    Present address: Cellestis Ltd., 1341 Dandenong Rd, Chadstone, VIC, 3148, Australia

Authors and Affiliations

  1. Ludwig Institute for Cancer Research Melbourne, Austin Branch, Austin Hospital, 145-163 Studley Road, Heidelberg, VIC, 3084, Australia

    Ashley J. Knights, Anupama Pasam & Jonathan Cebon

  2. Institute of Immunology, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic

    Jitka Fucikova

  3. CSL Limited, 45 Poplar Road Parkville, Melbourne, VIC, 3052, Australia

    Sandra Koernig

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Correspondence to Jonathan Cebon.

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Knights, A.J., Fucikova, J., Pasam, A. et al. Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. Cancer Immunol Immunother 62, 321–335 (2013). https://doi.org/10.1007/s00262-012-1342-1

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  • DOI: https://doi.org/10.1007/s00262-012-1342-1

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