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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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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. |
format | Online Article Text |
id | pubmed-7017151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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