Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma <i>in vitro</i>

Sauer, Maike; Reiners, Katrin S.; Hp, Hansen; Engert, Andreas; Gasser, Stephan; Ep, von Strandmann

doi:10.1515/hsz-2013-0161

Cited by 10 publications

(8 citation statements)

References 31 publications

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“…While the monovalent SM LCL161 has previously been reported to upregulate ligands for the activating NK cell receptor NKG2D such as MICA and MICB (49), we did not detect changes in NK cell receptor ligands on RMS cells upon treatment with the SM BV6, which might be due to different tumor types or different SM.…”

Section: Discussioncontrasting

confidence: 82%

The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells

et al. 2017

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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 (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.

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Section: Discussioncontrasting

confidence: 82%

The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells

et al. 2017

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“…Studies using LCL161 in combination with a pan Bcl2 family inhibitor such as obatoclax might therefore show synergistic activity in a MM setting. Furthermore, LCL161, by modulating the NF-κB pathway was shown to potentiate the anti-tumor activity of T cells and NK-cells without affecting their viabilities at concentrations comparable to ones used in our study (45, 46). However, using LCL161 with a cancer vaccine reduced the ability of dendritic cells to cross present the antigen and activate antigen specific immune response (45).…”

Section: Discussionsupporting

confidence: 51%

Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma

et al. 2014

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The inhibitor of apoptosis (IAP) proteins plays a critical role in the control of apoptotic machinery, and has been explored as a therapeutic target. Here, we have examined the functional importance of IAPs in multiple myeloma (MM) by using a Smac-mimetic LCL161. We observed that LCL161 was able to potently induce apoptosis in some MM cell lines but not in others. Examining the levels of XIAP, cIAP1 and cIAP2 post LCL161 treatment indicated clear down regulation of both XIAP activity and cIAP1 levels in both the sensitive and less sensitive (resistant) cell lines. cIAP2, however, was not down regulated in the cell line resistant to the drug. siRNA mediated silencing of cIAP2 significantly enhanced the effect of LCL161 indicating the importance of down regulating all IAPs simultaneously for induction of apopotsis in MM cells. LCL161 induced marked up regulation of the Jak2/Stat3 pathway in the resistant MM cell lines. Combining LCL161 with a Jak2 specific inhibitor resulted in synergistic cell death in MM cell lines and patient cells. In addition, combining LCL161 with death inducing ligands clearly showed that LCL161 sensitized MM cells to both FAS-L and TRAIL.

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“…SMCs also potentiate Hodgkin lymphoma (HL) cell death by NK cells (Brinkmann et al, 2014). In a separate study, a monovalent SMC induced the expression of ligands for the activating immune receptor NKG2D on HL cells, and enhanced the susceptibility of HL cells to NKG2D-dependent lysis by NK cells (Sauer et al, 2013).…”

Section: Smac Mimetic Synergy With Adoptive Immune-cell Therapy and Cmentioning

confidence: 99%

Combinatorial cancer immunotherapy strategies with proapoptotic small-molecule IAP antagonists

Beug

Conrad²,

Alain³

et al. 2015

Int. J. Dev. Biol.

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Members of the inhibitor of apoptosis (IAP) family control several critical aspects of innate immunity, cell death, and tumorigenesis. Small molecule antagonists that target specific IAP oncoproteins, primarily cIAP1 and cIAP2, but potentially also XIAP and Livin, modulate distinct immune signal transduction pathways that can lead to an increased sensitivity of tumors cells to cytokine-mediated apoptosis. These antagonists are based on the structure of an endogenous cellular IAP inhibitor called Smac. Smac is normally sequestered within the mitochondria and is released into the cytoplasm upon cell death stimuli, thereby overcoming the anti-apoptotic action of the IAPs. The therapeutic usefulness of recombinant tumoricidal cytokines to treat cancer patients is principally limited due to their unacceptable adverse side effects. Therefore, investigators have sought to develop alternative regimens that do not rely on exogenously delivered death ligands. These approaches include the stimulation of the immune system with oncolytic virus-based agents or Toll-like receptor agonists in combination with Smac mimetics. Similarly, preclinical combination immunotherapy studies reveal that recombinant interferon synergizes with Smac mimetics to kill cancer. This strategy opens up new therapeutic avenues for anti-cancer therapy by modulating specific immune-mediated death pathways employing unique dual-pronged combinatorial approaches.

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Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro

Cited by 10 publications

References 31 publications

The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells

The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells

Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma

Combinatorial cancer immunotherapy strategies with proapoptotic small-molecule IAP antagonists

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