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Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9–11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a...

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Autores principales: Lin, Grant L., Nagaraja, Surya, Filbin, Mariella G., Suvà, Mario L., Vogel, Hannes, Monje, Michelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022714/
https://www.ncbi.nlm.nih.gov/pubmed/29954445
http://dx.doi.org/10.1186/s40478-018-0553-x
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author Lin, Grant L.
Nagaraja, Surya
Filbin, Mariella G.
Suvà, Mario L.
Vogel, Hannes
Monje, Michelle
author_facet Lin, Grant L.
Nagaraja, Surya
Filbin, Mariella G.
Suvà, Mario L.
Vogel, Hannes
Monje, Michelle
author_sort Lin, Grant L.
collection PubMed
description Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9–11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM). We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b + macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0553-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-60227142018-07-09 Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma Lin, Grant L. Nagaraja, Surya Filbin, Mariella G. Suvà, Mario L. Vogel, Hannes Monje, Michelle Acta Neuropathol Commun Research Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9–11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM). We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b + macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0553-x) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-28 /pmc/articles/PMC6022714/ /pubmed/29954445 http://dx.doi.org/10.1186/s40478-018-0553-x Text en © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Lin, Grant L.
Nagaraja, Surya
Filbin, Mariella G.
Suvà, Mario L.
Vogel, Hannes
Monje, Michelle
Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
title Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
title_full Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
title_fullStr Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
title_full_unstemmed Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
title_short Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
title_sort non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022714/
https://www.ncbi.nlm.nih.gov/pubmed/29954445
http://dx.doi.org/10.1186/s40478-018-0553-x
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