The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells.
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 theex vivoexpansion 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.
University Hospital Frankfurt, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe University, Frankfurt, Germany; LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt, Germany.
Kyra
K
Fischer
University Hospital Frankfurt, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe University, Frankfurt, Germany; LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt, Germany.
Sara
S
Tognarelli
Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Stefanie
S
Roesler
Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cathinka
C
Boedicker
University Hospital Frankfurt, Department for Children and Adolescents Medicine, Goethe University, Frankfurt, Germany; University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Pulmonology, Allergy and Cystic Fibrosis, Goethe University, Frankfurt, Germany.
Ralf
R
Schubert
University Hospital Frankfurt, Department for Molecular Medicine, Goethe University , Frankfurt , Germany.
Alexander
A
Steinle
LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt, Germany; University Hospital Frankfurt, Department for Children and Adolescents Medicine, Goethe University, Frankfurt, Germany.
Thomas
T
Klingebiel
University Hospital Frankfurt, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe University, Frankfurt, Germany; LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt, Germany.
Peter
P
Bader
Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Simone
S
Fulda
University Hospital Frankfurt, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe University, Frankfurt, Germany; LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt, Germany.
Evelyn
E
Ullrich
BV6; RD cells; RH30 cells; natural killer cells; rhabdomyosarcoma; second mitochondria-derived activator of caspases mimetic