title: Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy.
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.
authors.affiliation: Ludwig Institute for Cancer Research Melbourne, Austin Branch, Austin Hospital, 145-163 Studley Road, Heidelberg, VIC, 3084, Australia. Ashley.Knights@ludwig.edu.au
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Knights
authors.forename: Jitka
authors.initials: J
authors.lastname: Fucikova
authors.forename: Anupama
authors.initials: A
authors.lastname: Pasam
authors.forename: Sandra
authors.initials: S
authors.lastname: Koernig
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019496:Cancer Vaccines / Q000494:pharmacology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D016328:NF-kappa B; D010455:Peptides; D013844:Thiazoles