2017
DOI: 10.3389/fimmu.2017.00202
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The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells

Abstract: Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines … Show more

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Cited by 23 publications
(31 citation statements)
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“…Previous studies suggest that IAP antagonists, in addition to their ability to enhance sensitivity to TNF-mediated apoptosis of cancer cells, are able to modulate diverse innate and adaptive anti-tumor immune responses. 8,18,20,21,25,26,42 Promising pre-clinical data across multiple cancer models and numerous ongoing clinical trials involving IAP antagonists (NCT02503423, NCT02649673, NCT03111992) highlight the great potential for combining these novel agents with chemotherapy, radiation and/or immunotherapies such as checkpoint inhibitors. 20,21,26 Despite significant advances in understanding how IAP antagonists enhance anti-tumor functions of immune cells, 20,21,25 the tumor-cell-intrinsic mechanisms involved in inducing these immune responses remain largely unexplored, particularly in HNSCC.…”
Section: Discussionmentioning
confidence: 99%
“…Previous studies suggest that IAP antagonists, in addition to their ability to enhance sensitivity to TNF-mediated apoptosis of cancer cells, are able to modulate diverse innate and adaptive anti-tumor immune responses. 8,18,20,21,25,26,42 Promising pre-clinical data across multiple cancer models and numerous ongoing clinical trials involving IAP antagonists (NCT02503423, NCT02649673, NCT03111992) highlight the great potential for combining these novel agents with chemotherapy, radiation and/or immunotherapies such as checkpoint inhibitors. 20,21,26 Despite significant advances in understanding how IAP antagonists enhance anti-tumor functions of immune cells, 20,21,25 the tumor-cell-intrinsic mechanisms involved in inducing these immune responses remain largely unexplored, particularly in HNSCC.…”
Section: Discussionmentioning
confidence: 99%
“…There have been several reports that IAP antagonists potentiate Hodgkin lymphoma susceptibility towards NK cell-mediated killing [97,98], and a TNF-dependent increase in the effector function of NK cells in vitro following the administration of birinapant has been reported [85]. Similarly, BV6 improves NK cell-mediated killing of rhabdomyosarcoma cells by sensitising them to NK cell-mediated killing through TNF, whilst simultaneously enhancing the cytotoxic potential of the NK cells through increasing NK cell activation [99]. Furthermore, the administration of AG-1387 resulted in a five-fold increase in NK cell tumour infiltration, as well as inducing tumour cell apoptosis directly in a hepatocellular carcinoma xenograph model [80].…”
Section: Role Of Smac-mimetics In Nk Cell-specific Immunotherapiesmentioning
confidence: 99%
“…Similarly, resistance to NK cell killing may be overcome by using SMAC mimetics, a new class of targeted drugs that act as IAP antagonists. SMAC mimetics increase NK cell proliferation in vitro and in vivo [120], increase cytotoxicity [121][122][123][124] and overcome rituximab resistance in preclinical models of B cell lymphoma [125]. Furthermore, SMAC mimetics sensitize sarcomas and hematological cancers to CIK cell adoptive therapy [126,127] and they have also demonstrated clinical efficacy in mouse models of glioblastoma and osteosarcoma, alone or in combination with checkpoint blockade [128,129].…”
Section: Hallmarks Of Cancer and Resistance To Nk Cell Immunotherapymentioning
confidence: 99%