TY  - JOUR
A1  - Särchen, Vinzenz
A1  - Shanmugalingam, Senthan
A1  - Kehr, Sarah
A1  - Reindl, Lisa Marie
A1  - Greze, Victoria
A1  - Wiedemann, Sara
A1  - Boedicker, Cathinka
A1  - Jacob, Maureen
A1  - Bankov, Katrin
A1  - Becker, Nina
A1  - Wehner, Sibylle
A1  - Theilen, Till-Martin
A1  - Gretser, Steffen
A1  - Gradhand, Elise
A1  - Kummerow, Carsten
A1  - Ullrich, Evelyn
A1  - Vogler, Meike
T1  - Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy
T2  - Cell death discovery
N2  - The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-XL inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-XL or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.
KW  - Paediatric cancer
KW  - Tumour immunology
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/69533
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-695330
SN  - 2058-7716
N1  - Open Access funding enabled and organized by Projekt DEAL.
N1  - This work has been supported by the Deutsche Forschungsgemeinschaft DFG (INST 256/423-1 FUGG)
VL  - 8
IS  - art. 11
SP  - 1
EP  - 10
PB  - Nature Publishing Group
CY  - London
ER  -