TY  - JOUR
AU  - Särchen, Vinzenz
AU  - Reindl, Lisa Marie
AU  - Wiedemann, Sara
AU  - Shanmugalingam, Senthan
AU  - Bukur, Thomas
AU  - Becker, Julia
AU  - Suchan, Martin
AU  - Ullrich, Evelyn
AU  - Vogler, Meike
TI  - Characterization of BV6-Induced Sensitization to the NK Cell Killing of Pediatric Rhabdomyosarcoma Spheroids.
JO  - Cells
VL  - 12
IS  - 6
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DKFZ-2023-00629
SP  - 906
PY  - 2023
AB  - Although the overall survival in pediatric rhabdomyosarcoma (RMS) has increased over the last decades, the most aggressive subtype of alveolar RMS is in dire need of novel treatment strategies. RMS cells evade cell death induction and immune control by increasing the expression of inhibitors of apoptosis proteins (IAPs), which can be exploited and targeted with stimulation with Smac mimetics. Here, we used the Smac mimetic BV6 to re-sensitize RMS spheroids to cell death, which increased killing induced by natural killer (NK) cells. Single BV6 treatment of RMS spheroids did not reduce spheroidal growth. However, we observed significant spheroidal decomposition upon BV6 pre-treatment combined with NK cell co-cultivation. Molecularly, IAPs s are rapidly degraded by BV6, which activates NF-κB signal transduction pathways in RMS spheroids. RNA sequencing analysis validated NF-κB activation and identified a plethora of BV6-regulated genes. Additionally, BV6 released caspases from IAP-mediated inhibition. Here, caspase-8 might play a major role, as knockdown experiments resulted in decreased NK cell-mediated attack. Taken together, we improved the understanding of the BV6 mechanism of RMS spheroid sensitization to cytotoxic immune cells, which could be suitable for the development of novel combinatory cellular immunotherapy with Smac mimetics.
KW  - BV6 (Other)
KW  - NK cells (Other)
KW  - Smac mimetic (Other)
KW  - cell death (Other)
KW  - rhabdomyosarcoma (Other)
KW  - tumor spheroids (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36980247
DO  - DOI:10.3390/cells12060906
UR  - https://inrepo02.dkfz.de/record/274486
ER  -