Uncovering the mode of action of engineered T cells in patient cancer organoids
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Published:2022-07-25
Issue:1
Volume:41
Page:60-69
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ISSN:1087-0156
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Container-title:Nature Biotechnology
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language:en
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Short-container-title:Nat Biotechnol
Author:
Dekkers Johanna F., Alieva Maria, Cleven Astrid, Keramati Farid, Wezenaar Amber K. L., van Vliet Esmée J.ORCID, Puschhof Jens, Brazda PeterORCID, Johanna Inez, Meringa Angelo D., Rebel Heggert G., Buchholz Maj-Britt, Barrera Román MarioORCID, Zeeman Amber L., de Blank SamORCID, Fasci Domenico, Geurts Maarten H., Cornel Annelisa M., Driehuis Else, Millen Rosemary, Straetemans Trudy, Nicolasen Mara J. T., Aarts-Riemens Tineke, Ariese Hendrikus C. R.ORCID, Johnson Hannah R., van Ineveld Ravian L., Karaiskaki Froso, Kopper Oded, Bar-Ephraim Yotam E., Kretzschmar KaiORCID, Eggermont Alexander M. M., Nierkens Stefan, Wehrens Ellen J., Stunnenberg Henk G.ORCID, Clevers HansORCID, Kuball JürgenORCID, Sebestyen ZsoltORCID, Rios Anne C.ORCID
Abstract
AbstractExtending the success of cellular immunotherapies against blood cancers to the realm of solid tumors will require improved in vitro models that reveal therapeutic modes of action at the molecular level. Here we describe a system, called BEHAV3D, developed to study the dynamic interactions of immune cells and patient cancer organoids by means of imaging and transcriptomics. We apply BEHAV3D to live-track >150,000 engineered T cells cultured with patient-derived, solid-tumor organoids, identifying a ‘super engager’ behavioral cluster comprising T cells with potent serial killing capacity. Among other T cell concepts we also study cancer metabolome-sensing engineered T cells (TEGs) and detect behavior-specific gene signatures that include a group of 27 genes with no previously described T cell function that are expressed by super engager killer TEGs. We further show that type I interferon can prime resistant organoids for TEG-mediated killing. BEHAV3D is a promising tool for the characterization of behavioral-phenotypic heterogeneity of cellular immunotherapies and may support the optimization of personalized solid-tumor-targeting cell therapies.
Funder
ZonMw KWF Kankerbestrijding St. Baldrick’s Foundation
Publisher
Springer Science and Business Media LLC
Subject
Biomedical Engineering,Molecular Medicine,Applied Microbiology and Biotechnology,Bioengineering,Biotechnology
Reference60 articles.
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