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In vitro lymph node-mimicking 3D model displays long-term T cell-dependent CLL proliferation and survival

View ORCID ProfileMarco Vincent Haselager, Bianca Francisca van Driel, Eduard Perelaer, Dennis de Rooij, Danial Lashgari, View ORCID ProfileRemco Loos, View ORCID ProfileArnon P. Kater, View ORCID ProfilePerry D. Moerland, View ORCID ProfileEric Eldering
doi: https://doi.org/10.1101/2023.04.03.535388
Marco Vincent Haselager
1Departments of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
4Lymphoma and Myeloma, Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands
5Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands
6Cancer Immunology, Amsterdam, The Netherlands
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Bianca Francisca van Driel
2Hematology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
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Eduard Perelaer
1Departments of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
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Dennis de Rooij
2Hematology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
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Danial Lashgari
3Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
6Cancer Immunology, Amsterdam, The Netherlands
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Remco Loos
9Center for Innovation and Translational Research Europe, Bristol Myers Squibb, Sevilla, Spain
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Arnon P. Kater
2Hematology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
4Lymphoma and Myeloma, Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands
5Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands
6Cancer Immunology, Amsterdam, The Netherlands
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Perry D. Moerland
3Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
7Inflammatory Diseases, Amsterdam, The Netherlands
8Amsterdam Public Health, Methodology Amsterdam, The Netherlands
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Eric Eldering
1Departments of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
4Lymphoma and Myeloma, Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands
5Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands
6Cancer Immunology, Amsterdam, The Netherlands
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  • For correspondence: e.eldering@amsterdamumc.nl
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Abstract

Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironmental cells and signals. The lymph node (LN) is the critical site of in vivo CLL proliferation and development of resistance to both chemotherapy and targeted agents. We present a new model that incorporates key aspects of the CLL LN which enables investigation of CLL cells in the context of a protective niche. We describe a 3D in vitro culture system utilizing ultra-low attachment (ULA) plates to create spheroids of CLL cells derived from peripheral blood (PB). Starting from CLL:T cell ratios as observed in LN samples, CLL activation was induced by either direct stimulation and/or indirectly via T cells. Compared to 2D cultures, 3D cultures promoted CLL proliferation in a T cell-dependent manner, and enabled expansion for up to 7 weeks, including the formation of follicle-like structures after several weeks of culture. Addition of LN-derived stromal cells further enhanced the proliferative capacity. This model enables high-throughput drug screening, of which we describe response to Btk inhibition, venetoclax resistance, and T cell-mediated cytotoxicity as examples. In summary, we present the first LN-mimicking in vitro 3D culture for primary CLL, which enables readouts such as real-time drug screens, kinetic growth assays and spatial localization. This is the first in vitro CLL system that allows testing of response and resistance to venetoclax and Btk inhibitors in the context of the tumor microenvironment, thereby opening up new possibilities for clinically useful applications.

Competing Interest Statement

R. Loos is an employee and equity holder of Bristol Myers Squibb.

Footnotes

  • Disclosures R. Loos is an employee and equity holder of Bristol Myers Squibb.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 05, 2023.
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In vitro lymph node-mimicking 3D model displays long-term T cell-dependent CLL proliferation and survival
Marco Vincent Haselager, Bianca Francisca van Driel, Eduard Perelaer, Dennis de Rooij, Danial Lashgari, Remco Loos, Arnon P. Kater, Perry D. Moerland, Eric Eldering
bioRxiv 2023.04.03.535388; doi: https://doi.org/10.1101/2023.04.03.535388
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In vitro lymph node-mimicking 3D model displays long-term T cell-dependent CLL proliferation and survival
Marco Vincent Haselager, Bianca Francisca van Driel, Eduard Perelaer, Dennis de Rooij, Danial Lashgari, Remco Loos, Arnon P. Kater, Perry D. Moerland, Eric Eldering
bioRxiv 2023.04.03.535388; doi: https://doi.org/10.1101/2023.04.03.535388

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