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Uncovering the mode of action of engineered T cells in patient cancer organoids.

ABSTRACT: 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.

SUBMITTER: Dekkers JF

PROVIDER: S-EPMC9849137 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Uncovering the mode of action of engineered T cells in patient cancer organoids.

Dekkers Johanna F JF Alieva Maria M Cleven Astrid A Keramati Farid F Wezenaar Amber K L AKL van Vliet Esmée J EJ Puschhof Jens J Brazda Peter P Johanna Inez I Meringa Angelo D AD Rebel Heggert G HG Buchholz Maj-Britt MB Barrera Román Mario M Zeeman Amber L AL de Blank Sam S Fasci Domenico D Geurts Maarten H MH Cornel Annelisa M AM Driehuis Else E Millen Rosemary R Straetemans Trudy T Nicolasen Mara J T MJT Aarts-Riemens Tineke T Ariese Hendrikus C R HCR Johnson Hannah R HR van Ineveld Ravian L RL Karaiskaki Froso F Kopper Oded O Bar-Ephraim Yotam E YE Kretzschmar Kai K Eggermont Alexander M M AMM Nierkens Stefan S Wehrens Ellen J EJ Stunnenberg Henk G HG Clevers Hans H Kuball Jürgen J Sebestyen Zsolt Z Rios Anne C AC

Nature biotechnology 20220725 1

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 ...[more]

PMID: 35879361

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Project description:BackgroundStudies over the past decade and half have identified cancer stem cells (CSCs) to be responsible for tumorigenesis, invasion, sustenance of metastatic disease, radio- and chemo-resistance and tumor relapse. Recent reports have described the plasticity of breast CSCs (BCSCs) to shift between the epithelial and mesenchymal phenotypes via Epithelial-Mesenchymal Transition (EMT) and Mesenchymal-Epithelial Transition (MET) states as the reason for their invasive capabilities. Additionally, BRCA1 has been found to be a mammary stem cell fate determinant. However, it is not clear what would be the best marker that can be used for identifying CSCs in BRCA1 mutated cancers. Also, anticancer agents that can reduce CSC population in a BRCA1 defective condition have not been addressed so far.MethodsPutative BCSCs were identified based on Hoechst exclusion, CD44(+)/24(-/low) expression and Aldehyde Dehydrogenase 1 (ALDH1) positivity using flow cytometry. The 'stemness' of the isolated ALDH1+ cells were analysed by immunofluorescence, western blotting for stem cell and EMT markers as well as in vitro mammosphere assays. Induction of Reactive Oxygen Species (ROS) by Plumbagin (PB) in BCSCs was assayed by Dichloro-dihydro-fluorescein diacetate (DCF-DA) staining. Ovarian cancer xenografts treated with PB were subjected to immunohistochemical analysis to study the ability of PB to target CSCs.ResultsWe have confirmed that ALDH1 positivity is the best marker for the identification of BCSCs in BRCA1-defective breast cancer cell lines when compared to the CD marker profile and Side Population (SP) analysis. BRCA1 status was observed to be a determinant of the abundance of epithelial-like (ALDH1+) or mesenchymal-like (CD44(+)/24(-/low)) BCSCs, and the reconstitution of a full length, wild type BRCA1 in HCC1937 breast cancer cells possessing a mutated BRCA1, transforms them from 'stem-like' to more 'mesenchymal'. For the first time we have shown that Plumbagin (PB), a naturally occurring naphthoquinone which is predominantly a ROS inducer, could reduce BCSCs specifically in BRCA1-defective, basal-like cancer cells.ConclusionsThe best marker for identifying BCSCs in BRCA1 defective condition could be ALDH1 and that BRCA1 mutated BCSCs would be mostly 'stem like' than 'mesenchymal'. Also ROS inducers like PB could reduce BCSCs in BRCA1 defective cancers.

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Uncovering the mode of action of engineered T cells in patient cancer organoids.

Publications

Uncovering the mode of action of engineered T cells in patient cancer organoids.

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