Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma

Shawn T. Beug, Caroline E. Beauregard, Cristin Healy, Tarun Sanda, Martine St-Jean, Janelle Chabot, Danielle E. Walker, Aditya Mohan, Nathalie Earl, Xueqing Lun, Donna L. Senger, Stephen M. Robbins, Peter Staeheli, Peter A. Forsyth, Tommy Alain, Eric C. LaCasse () and Robert G. Korneluk ()
Additional contact information
Shawn T. Beug: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Caroline E. Beauregard: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Cristin Healy: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Tarun Sanda: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Martine St-Jean: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Janelle Chabot: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Danielle E. Walker: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Aditya Mohan: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Nathalie Earl: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Xueqing Lun: Arnie Charbonneau Cancer Institute, University of Calgary
Donna L. Senger: Arnie Charbonneau Cancer Institute, University of Calgary
Stephen M. Robbins: Arnie Charbonneau Cancer Institute, University of Calgary
Peter Staeheli: Institute of Virology, University Medical Center Freiburg
Peter A. Forsyth: H. Lee Moffit Cancer Center and Research Institute
Tommy Alain: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Eric C. LaCasse: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute
Robert G. Korneluk: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14278

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