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

Autor: Särchen V; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany., Shanmugalingam S; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany., Kehr S; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany., Reindl LM; Children's Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Experimental Immunology, Goethe-University Frankfurt, Frankfurt am Main, Germany., Greze V; Children's Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Experimental Immunology, Goethe-University Frankfurt, Frankfurt am Main, Germany., Wiedemann S; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany., Boedicker C; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany., Jacob M; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany., Bankov K; Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt am Main, Germany., Becker N; Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt am Main, Germany.; University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt am Main, Germany., Wehner S; Children's Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany., Theilen TM; Department of Pediatric Surgery and Pediatric Urology, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt am Main, Germany., Gretser S; Department of Pediatric and Perinatal Pathology, Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt am Main, Germany., Gradhand E; Department of Pediatric and Perinatal Pathology, Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt am Main, Germany., Kummerow C; Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Saarland, Germany., Ullrich E; Children's Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Experimental Immunology, Goethe-University Frankfurt, Frankfurt am Main, Germany.; University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt am Main, Germany.; Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt am Main, Germany.; German Cancer Consortium (DKTK) partner site Frankfurt/Mainz, Frankfurt am Main, Germany., Vogler M; Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany. m.vogler@kinderkrebsstiftung-frankfurt.de.; German Cancer Consortium (DKTK) partner site Frankfurt/Mainz, Frankfurt am Main, Germany. m.vogler@kinderkrebsstiftung-frankfurt.de.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2022 Jan 10; Vol. 8 (1), pp. 11. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41420-021-00812-6
Abstrakt: 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-X L 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-X L or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: