Cargando…

Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy

Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%–40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor pr...

Descripción completa

Detalles Bibliográficos
Autores principales: Foxall, Russell, Narang, Priyanka, Glaysher, Bridget, Hub, Elin, Teal, Emma, Coles, Mark C., Ashton-Key, Margaret, Beers, Stephen A., Cragg, Mark S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897703/
https://www.ncbi.nlm.nih.gov/pubmed/33628205
http://dx.doi.org/10.3389/fimmu.2020.605231
_version_ 1783653721339592704
author Foxall, Russell
Narang, Priyanka
Glaysher, Bridget
Hub, Elin
Teal, Emma
Coles, Mark C.
Ashton-Key, Margaret
Beers, Stephen A.
Cragg, Mark S.
author_facet Foxall, Russell
Narang, Priyanka
Glaysher, Bridget
Hub, Elin
Teal, Emma
Coles, Mark C.
Ashton-Key, Margaret
Beers, Stephen A.
Cragg, Mark S.
author_sort Foxall, Russell
collection PubMed
description Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%–40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM.
format Online
Article
Text
id pubmed-7897703
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-78977032021-02-23 Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy Foxall, Russell Narang, Priyanka Glaysher, Bridget Hub, Elin Teal, Emma Coles, Mark C. Ashton-Key, Margaret Beers, Stephen A. Cragg, Mark S. Front Immunol Immunology Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%–40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM. Frontiers Media S.A. 2021-02-08 /pmc/articles/PMC7897703/ /pubmed/33628205 http://dx.doi.org/10.3389/fimmu.2020.605231 Text en Copyright © 2021 Foxall, Narang, Glaysher, Hub, Teal, Coles, Ashton-Key, Beers and Cragg http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Foxall, Russell
Narang, Priyanka
Glaysher, Bridget
Hub, Elin
Teal, Emma
Coles, Mark C.
Ashton-Key, Margaret
Beers, Stephen A.
Cragg, Mark S.
Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy
title Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy
title_full Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy
title_fullStr Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy
title_full_unstemmed Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy
title_short Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy
title_sort developing a 3d b cell lymphoma culture system to model antibody therapy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897703/
https://www.ncbi.nlm.nih.gov/pubmed/33628205
http://dx.doi.org/10.3389/fimmu.2020.605231
work_keys_str_mv AT foxallrussell developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT narangpriyanka developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT glaysherbridget developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT hubelin developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT tealemma developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT colesmarkc developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT ashtonkeymargaret developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT beersstephena developinga3dbcelllymphomaculturesystemtomodelantibodytherapy
AT craggmarks developinga3dbcelllymphomaculturesystemtomodelantibodytherapy