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Title: | Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. | Austin Authors: | Knights, Ashley J;Fucikova, Jitka;Pasam, Anupama;Koernig, Sandra;Cebon, Jonathan S | Affiliation: | Ashley.Knights@ludwig.edu.au Ludwig Institute for Cancer Research Melbourne, Austin Branch, Austin Hospital, 145-163 Studley Road, Heidelberg, VIC, 3084, Australia |
Issue Date: | 26-Aug-2012 | Publication information: | Cancer Immunology, Immunotherapy : Cii 2012; 62(2): 321-35 | 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. | Gov't Doc #: | 22923192 | URI: | http://ahro.austin.org.au/austinjspui/handle/1/11550 | DOI: | 10.1007/s00262-012-1342-1 | Journal: | Cancer immunology, immunotherapy : CII | URL: | https://pubmed.ncbi.nlm.nih.gov/22923192 | Type: | Journal Article | Subjects: | Antigens, Neoplasm.immunology.pharmacology Antineoplastic Agents.pharmacology Apoptosis.drug effects Cancer Vaccines.pharmacology Cells, Cultured Combined Modality Therapy Cytokines.secretion Dendritic Cells.drug effects.immunology Humans Immunotherapy Inhibitor of Apoptosis Proteins.antagonists & inhibitors Leukocytes, Mononuclear.drug effects.immunology NF-kappa B.metabolism Peptides.pharmacology T-Lymphocytes.drug effects.immunology Thiazoles.pharmacology Up-Regulation.drug effects |
Appears in Collections: | Journal articles |
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