Immune characterization of pre-clinical murine models of neuroblastoma

Abstract Immunotherapy offers a potentially less toxic, more tumor-specific treatment for neuroblastoma than conventional cytotoxic therapies. Accurate and reproducible immune competent preclinical models are key to understanding mechanisms of action, interactions with other therapies and mechanisms...

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Autores principales:	Emily R. Webb, Silvia Lanati, Carol Wareham, Alistair Easton, Stuart N. Dunn, Tatyana Inzhelevskaya, Freja M. Sadler, Sonya James, Margaret Ashton-Key, Mark S. Cragg, Stephen A. Beers, Juliet C. Gray
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1cd179c8bd0e4a0ba1a1db6fa9ea0186
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spelling	oai:doaj.org-article:1cd179c8bd0e4a0ba1a1db6fa9ea01862021-12-02T18:37:06ZImmune characterization of pre-clinical murine models of neuroblastoma10.1038/s41598-020-73695-92045-2322https://doaj.org/article/1cd179c8bd0e4a0ba1a1db6fa9ea01862020-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-73695-9https://doaj.org/toc/2045-2322Abstract Immunotherapy offers a potentially less toxic, more tumor-specific treatment for neuroblastoma than conventional cytotoxic therapies. Accurate and reproducible immune competent preclinical models are key to understanding mechanisms of action, interactions with other therapies and mechanisms of resistance to immunotherapy. Here we characterized the tumor and splenic microenvironment of two syngeneic subcutaneous (NXS2 and 9464D), and a spontaneous transgenic (TH-MYCN) murine model of neuroblastoma, comparing histological features and immune infiltrates to previously published data on human neuroblastoma. Histological sections of frozen tissues were stained by immunohistochemistry and immunofluorescence for immune cell markers and tumor architecture. Tissues were dissociated by enzymatic digestion, stained with panels of antibodies to detect and quantify cancer cells, along with lymphocytic and myeloid infiltration by flow cytometry. Finally, we tested TH-MYCN mice as a feasible model for immunotherapy, using prior treatment with cyclophosphamide to create a therapeutic window of minimal residual disease to favor host immune development. Immune infiltration differed significantly between all the models. TH-MYCN tumors were found to resemble immune infiltration in human tumors more closely than the subcutaneous models, alongside similar GD2 and MHC class I expression. Finally, TH-MYCN transgenic mice were administered cyclophosphamide alone or in combination with an anti-GD2 or anti-4-1BB monoclonal antibody, which resulted in increase in survival in both combination therapies. The TH-MYCN transgenic mouse is a promising in vivo model for testing immunotherapy compounds and combination therapy in a preclinical setting.Emily R. WebbSilvia LanatiCarol WarehamAlistair EastonStuart N. DunnTatyana InzhelevskayaFreja M. SadlerSonya JamesMargaret Ashton-KeyMark S. CraggStephen A. BeersJuliet C. GrayNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-17 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emily R. Webb Silvia Lanati Carol Wareham Alistair Easton Stuart N. Dunn Tatyana Inzhelevskaya Freja M. Sadler Sonya James Margaret Ashton-Key Mark S. Cragg Stephen A. Beers Juliet C. Gray Immune characterization of pre-clinical murine models of neuroblastoma
description	Abstract Immunotherapy offers a potentially less toxic, more tumor-specific treatment for neuroblastoma than conventional cytotoxic therapies. Accurate and reproducible immune competent preclinical models are key to understanding mechanisms of action, interactions with other therapies and mechanisms of resistance to immunotherapy. Here we characterized the tumor and splenic microenvironment of two syngeneic subcutaneous (NXS2 and 9464D), and a spontaneous transgenic (TH-MYCN) murine model of neuroblastoma, comparing histological features and immune infiltrates to previously published data on human neuroblastoma. Histological sections of frozen tissues were stained by immunohistochemistry and immunofluorescence for immune cell markers and tumor architecture. Tissues were dissociated by enzymatic digestion, stained with panels of antibodies to detect and quantify cancer cells, along with lymphocytic and myeloid infiltration by flow cytometry. Finally, we tested TH-MYCN mice as a feasible model for immunotherapy, using prior treatment with cyclophosphamide to create a therapeutic window of minimal residual disease to favor host immune development. Immune infiltration differed significantly between all the models. TH-MYCN tumors were found to resemble immune infiltration in human tumors more closely than the subcutaneous models, alongside similar GD2 and MHC class I expression. Finally, TH-MYCN transgenic mice were administered cyclophosphamide alone or in combination with an anti-GD2 or anti-4-1BB monoclonal antibody, which resulted in increase in survival in both combination therapies. The TH-MYCN transgenic mouse is a promising in vivo model for testing immunotherapy compounds and combination therapy in a preclinical setting.
format	article
author	Emily R. Webb Silvia Lanati Carol Wareham Alistair Easton Stuart N. Dunn Tatyana Inzhelevskaya Freja M. Sadler Sonya James Margaret Ashton-Key Mark S. Cragg Stephen A. Beers Juliet C. Gray
author_facet	Emily R. Webb Silvia Lanati Carol Wareham Alistair Easton Stuart N. Dunn Tatyana Inzhelevskaya Freja M. Sadler Sonya James Margaret Ashton-Key Mark S. Cragg Stephen A. Beers Juliet C. Gray
author_sort	Emily R. Webb
title	Immune characterization of pre-clinical murine models of neuroblastoma
title_short	Immune characterization of pre-clinical murine models of neuroblastoma
title_full	Immune characterization of pre-clinical murine models of neuroblastoma
title_fullStr	Immune characterization of pre-clinical murine models of neuroblastoma
title_full_unstemmed	Immune characterization of pre-clinical murine models of neuroblastoma
title_sort	immune characterization of pre-clinical murine models of neuroblastoma
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/1cd179c8bd0e4a0ba1a1db6fa9ea0186
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Immune characterization of pre-clinical murine models of neuroblastoma

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