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CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

OBJECTIVES: The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. METHODS: Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast can...

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Autores principales: Ramos, Rodrigo Nalio, Rodriguez, Céline, Hubert, Margaux, Ardin, Maude, Treilleux, Isabelle, Ries, Carola H, Lavergne, Emilie, Chabaud, Sylvie, Colombe, Amélie, Trédan, Olivier, Guedes, Henrique Gomes, Laginha, Fábio, Richer, Wilfrid, Piaggio, Eliane, Barbuto, José Alexandre M, Caux, Christophe, Ménétrier‐Caux, Christine, Bendriss‐Vermare, Nathalie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017151/
https://www.ncbi.nlm.nih.gov/pubmed/32082570
http://dx.doi.org/10.1002/cti2.1108
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author Ramos, Rodrigo Nalio
Rodriguez, Céline
Hubert, Margaux
Ardin, Maude
Treilleux, Isabelle
Ries, Carola H
Lavergne, Emilie
Chabaud, Sylvie
Colombe, Amélie
Trédan, Olivier
Guedes, Henrique Gomes
Laginha, Fábio
Richer, Wilfrid
Piaggio, Eliane
Barbuto, José Alexandre M
Caux, Christophe
Ménétrier‐Caux, Christine
Bendriss‐Vermare, Nathalie
author_facet Ramos, Rodrigo Nalio
Rodriguez, Céline
Hubert, Margaux
Ardin, Maude
Treilleux, Isabelle
Ries, Carola H
Lavergne, Emilie
Chabaud, Sylvie
Colombe, Amélie
Trédan, Olivier
Guedes, Henrique Gomes
Laginha, Fábio
Richer, Wilfrid
Piaggio, Eliane
Barbuto, José Alexandre M
Caux, Christophe
Ménétrier‐Caux, Christine
Bendriss‐Vermare, Nathalie
author_sort Ramos, Rodrigo Nalio
collection PubMed
description OBJECTIVES: The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. METHODS: Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro. Additionally, we used transcriptomic analysis to evaluate BC patients’ blood monocytes profiles. RESULTS: We observed that high intra‐tumor CD163‐expressing TAM density is predictive of reduced survival in BC patients. In vitro, M‐CSF, TGF‐β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163(high)CD86(low)IL‐10(high) M2‐like MΦ that strongly suppressed CD4(+) T‐cell expansion via PD‐L1 and IL‐10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type‐1 MΦ (M1‐MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic‐related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de‐activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1‐MΦ differentiation showed up‐regulation of IFN‐response genes and had no signs of metabolic alteration. CONCLUSION: Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro‐metastatic profile, resulting in the accumulation of further polarised CD163(high) TAMs resembling type‐2 MΦ (M2‐MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions.
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spelling pubmed-70171512020-02-20 CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes Ramos, Rodrigo Nalio Rodriguez, Céline Hubert, Margaux Ardin, Maude Treilleux, Isabelle Ries, Carola H Lavergne, Emilie Chabaud, Sylvie Colombe, Amélie Trédan, Olivier Guedes, Henrique Gomes Laginha, Fábio Richer, Wilfrid Piaggio, Eliane Barbuto, José Alexandre M Caux, Christophe Ménétrier‐Caux, Christine Bendriss‐Vermare, Nathalie Clin Transl Immunology Original Article OBJECTIVES: The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. METHODS: Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro. Additionally, we used transcriptomic analysis to evaluate BC patients’ blood monocytes profiles. RESULTS: We observed that high intra‐tumor CD163‐expressing TAM density is predictive of reduced survival in BC patients. In vitro, M‐CSF, TGF‐β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163(high)CD86(low)IL‐10(high) M2‐like MΦ that strongly suppressed CD4(+) T‐cell expansion via PD‐L1 and IL‐10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type‐1 MΦ (M1‐MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic‐related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de‐activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1‐MΦ differentiation showed up‐regulation of IFN‐response genes and had no signs of metabolic alteration. CONCLUSION: Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro‐metastatic profile, resulting in the accumulation of further polarised CD163(high) TAMs resembling type‐2 MΦ (M2‐MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions. John Wiley and Sons Inc. 2020-02-13 /pmc/articles/PMC7017151/ /pubmed/32082570 http://dx.doi.org/10.1002/cti2.1108 Text en © 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Ramos, Rodrigo Nalio
Rodriguez, Céline
Hubert, Margaux
Ardin, Maude
Treilleux, Isabelle
Ries, Carola H
Lavergne, Emilie
Chabaud, Sylvie
Colombe, Amélie
Trédan, Olivier
Guedes, Henrique Gomes
Laginha, Fábio
Richer, Wilfrid
Piaggio, Eliane
Barbuto, José Alexandre M
Caux, Christophe
Ménétrier‐Caux, Christine
Bendriss‐Vermare, Nathalie
CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
title CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
title_full CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
title_fullStr CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
title_full_unstemmed CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
title_short CD163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
title_sort cd163(+) tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017151/
https://www.ncbi.nlm.nih.gov/pubmed/32082570
http://dx.doi.org/10.1002/cti2.1108
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