TY - JOUR
T1 - Uncovering the mode of action of engineered T cells in patient cancer organoids
AU - Dekkers, Johanna F.
AU - Alieva, Maria
AU - Cleven, Astrid
AU - Keramati, Farid
AU - Wezenaar, Amber K.L.
AU - van Vliet, Esmée J.
AU - Puschhof, Jens
AU - Brazda, Peter
AU - Johanna, Inez
AU - Meringa, Angelo D.
AU - Rebel, Heggert G.
AU - Buchholz, Maj Britt
AU - Barrera Román, Mario
AU - Zeeman, Amber L.
AU - de Blank, Sam
AU - Fasci, Domenico
AU - Geurts, Maarten H.
AU - Cornel, Annelisa M.
AU - Driehuis, Else
AU - Millen, Rosemary
AU - Straetemans, Trudy
AU - Nicolasen, Mara J.T.
AU - Aarts-Riemens, Tineke
AU - Ariese, Hendrikus C.R.
AU - Johnson, Hannah R.
AU - van Ineveld, Ravian L.
AU - Karaiskaki, Froso
AU - Kopper, Oded
AU - Bar-Ephraim, Yotam E.
AU - Kretzschmar, Kai
AU - Eggermont, Alexander M.M.
AU - Nierkens, Stefan
AU - Wehrens, Ellen J.
AU - Stunnenberg, Henk G.
AU - Clevers, Hans
AU - Kuball, Jürgen
AU - Sebestyen, Zsolt
AU - Rios, Anne C.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - Extending 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.
AB - Extending 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.
UR - http://www.scopus.com/inward/record.url?scp=85134661174&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/be8588a1-db52-334a-aa8e-f2f7c5006494/
U2 - 10.1038/s41587-022-01397-w
DO - 10.1038/s41587-022-01397-w
M3 - Article
AN - SCOPUS:85134661174
SN - 1087-0156
JO - Nature Biotechnology
JF - Nature Biotechnology
ER -