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The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Peter MacCallum Cancer Centre, Melbourne, VI 3000, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, VI 3010, Australia
The Walter and Eliza Hall Institute of Medical Research, VI 3010, Australia
Department of Medical Biology, University of Melbourne, Parkville, VI 3010, Australia
Department of Immunology, Monash University, Melbourne, VI 3004, Australia
Author to whom correspondence should be addressed.
Cells 2020, 9(1), 207;
Received: 29 November 2019 / Revised: 6 January 2020 / Accepted: 11 January 2020 / Published: 14 January 2020
(This article belongs to the Special Issue Inhibitor of Apoptosis Proteins (IAPs) in Cancer Therapy)
One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed. View Full-Text
Keywords: smac-mimetics; TNF; cancer immunotherapy; checkpoint blockade; CAR T cells smac-mimetics; TNF; cancer immunotherapy; checkpoint blockade; CAR T cells
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Michie, J.; Kearney, C.J.; Hawkins, E.D.; Silke, J.; Oliaro, J. The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy. Cells 2020, 9, 207.

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