Abstract:
:Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Beug ST,Beauregard CE,Healy C,Sanda T,St-Jean M,Chabot J,Walker DE,Mohan A,Earl N,Lun X,Senger DL,Robbins SM,Staeheli P,Forsyth PA,Alain T,LaCasse EC,Korneluk RGdoi
10.1038/ncomms14278subject
Has Abstractpub_date
2017-02-15 00:00:00issn
2041-1723pii
ncomms14278journal_volume
8pub_type
杂志文章abstract::Plant diseases caused by fungi and oomycetes pose an increasing threat to food security and ecosystem health worldwide. These filamentous pathogens, while taxonomically distinct, modulate host defense responses by secreting effectors, which are typically identified based on the presence of signal peptides. Here we sho...
journal_title:Nature communications
pub_type: 杂志文章
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pub_type: 已发布勘误
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