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Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach

BACKGROUND: Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. METHODS: Here, we investigated TME heterogeneity within ea...

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Autores principales: Bareche, Yacine, Buisseret, Laurence, Gruosso, Tina, Girard, Edwina, Venet, David, Dupont, Floriane, Desmedt, Christine, Larsimont, Denis, Park, Morag, Rothé, Françoise, Stagg, John, Sotiriou, Christos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357326/
https://www.ncbi.nlm.nih.gov/pubmed/31665482
http://dx.doi.org/10.1093/jnci/djz208
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author Bareche, Yacine
Buisseret, Laurence
Gruosso, Tina
Girard, Edwina
Venet, David
Dupont, Floriane
Desmedt, Christine
Larsimont, Denis
Park, Morag
Rothé, Françoise
Stagg, John
Sotiriou, Christos
author_facet Bareche, Yacine
Buisseret, Laurence
Gruosso, Tina
Girard, Edwina
Venet, David
Dupont, Floriane
Desmedt, Christine
Larsimont, Denis
Park, Morag
Rothé, Françoise
Stagg, John
Sotiriou, Christos
author_sort Bareche, Yacine
collection PubMed
description BACKGROUND: Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. METHODS: Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided. RESULTS: We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism. CONCLUSIONS: Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.
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spelling pubmed-73573262020-07-16 Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach Bareche, Yacine Buisseret, Laurence Gruosso, Tina Girard, Edwina Venet, David Dupont, Floriane Desmedt, Christine Larsimont, Denis Park, Morag Rothé, Françoise Stagg, John Sotiriou, Christos J Natl Cancer Inst Articles BACKGROUND: Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. METHODS: Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided. RESULTS: We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism. CONCLUSIONS: Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients. Oxford University Press 2019-10-29 /pmc/articles/PMC7357326/ /pubmed/31665482 http://dx.doi.org/10.1093/jnci/djz208 Text en © The Author(s) 2019. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
Bareche, Yacine
Buisseret, Laurence
Gruosso, Tina
Girard, Edwina
Venet, David
Dupont, Floriane
Desmedt, Christine
Larsimont, Denis
Park, Morag
Rothé, Françoise
Stagg, John
Sotiriou, Christos
Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
title Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
title_full Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
title_fullStr Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
title_full_unstemmed Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
title_short Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
title_sort unraveling triple-negative breast cancer tumor microenvironment heterogeneity: towards an optimized treatment approach
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357326/
https://www.ncbi.nlm.nih.gov/pubmed/31665482
http://dx.doi.org/10.1093/jnci/djz208
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