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 (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.
Highlights
Cancer is the second leading cause of death in children after accidents [1]
Since immune effector cells including NK cells mainly function by inducing apoptosis in their targets, the efficacy of immunotherapy critically depends on intact apoptosis signaling pathways within the targeted cancer cells
We report that Smac mimetics (SM), which antagonize (X-linked/cellular) inhibitor of apoptosis proteins (IAPs) proteins, can prime RMS cells toward NK cellmediated cytotoxicity, and increase the cytotoxic potential of NK cells toward RH30 cells
Summary
Cancer is the second leading cause of death in children after accidents [1]. The most common type of cancer is leukemia, followed by cancer of the brain and nervous system, and soft tissue sarcomas including rhabdomyosarcomas (RMS) [2]. The survival of pediatric cancer has improved through progress in treatment [1, 3]. The outcome greatly depends on the type of cancer. RMS ranks second to last in the 5-year survival rate, four out of five high-risk patients are defeated by their disease [4, 5]. The histological subgroup referred to as alveolar RMS (ARMS) is known for its aggressive growth, while embryonal sarcomas (ERMS) are correlated to a slightly better outcome [3]. The low overall survival rate is due to resistance against established therapy regimens comprising chemo- and radiotherapy in first place or relapse after initial therapy, underlining the necessity of new treatment approaches.
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