Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma
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
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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Nature Communications. - 8 (2017) , ISSN: 2041-1723
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
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Universität
- (wann)
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2019
- Urheber
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Beug, Shawn T.
Beauregard, Caroline E.
Healy, Cristin
Sanda, Tarun
St-Jean, Martine
Chabot, Janelle
Walker, Danielle E.
Mohan, Aditya
Earl, Nathalie
Lun, Xueqing
Senger, Donna L.
Robbins, Stephen M.
Stäheli, Peter
Forsyth, Peter A.
Alain, Tommy
LaCasse, Eric C.
Korneluk, Robert G.
- DOI
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10.1038/ncomms14278
- URN
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urn:nbn:de:bsz:25-freidok-1369642
- Rechteinformation
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Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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2025-08-14T10:55:57+0200
Datenpartner
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Beteiligte
- Beug, Shawn T.
- Beauregard, Caroline E.
- Healy, Cristin
- Sanda, Tarun
- St-Jean, Martine
- Chabot, Janelle
- Walker, Danielle E.
- Mohan, Aditya
- Earl, Nathalie
- Lun, Xueqing
- Senger, Donna L.
- Robbins, Stephen M.
- Stäheli, Peter
- Forsyth, Peter A.
- Alain, Tommy
- LaCasse, Eric C.
- Korneluk, Robert G.
- Universität
Entstanden
- 2019
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