Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy

  • 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.
Author:Vinzenz SärchenORCiDGND, Senthan Shanmugalingam, Sarah KehrGND, Lisa Marie ReindlORCiD, Victoria Greze, Sara Wiedemann, Cathinka BoedickerORCiDGND, Maureen Jacob, Katrin BankovORCiDGND, Nina Becker, Sibylle WehnerGND, Till-Martin TheilenORCiDGND, Steffen GretserORCiDGND, Elise GradhandORCiDGND, Carsten KummerowORCiD, Evelyn UllrichORCiDGND, Meike VoglerORCiDGND
Parent Title (English):Cell death discovery
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Date of Publication (online):2022/01/10
Date of first Publication:2022/01/10
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/07/13
Tag:Paediatric cancer; Tumour immunology
Issue:art. 11
Article Number:11
Page Number:10
First Page:1
Last Page:10
Open Access funding enabled and organized by Projekt DEAL.
This work has been supported by the Deutsche Forschungsgemeinschaft DFG (INST 256/423-1 FUGG)
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International