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

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Ramos, Rodrigo Nalio [1, 2] ; Rodriguez, Celine [2] ; Hubert, Margaux [2] ; Ardin, Maude [2] ; Treilleux, Isabelle [3] ; Ries, Carola H. [4] ; Lavergne, Emilie [3] ; Chabaud, Sylvie [3] ; Colombe, Amelie [3] ; Tredan, Olivier [3] ; Guedes, Henrique Gomes [5] ; Laginha, Fabio [5] ; Richer, Wilfrid [6, 7] ; Piaggio, Eliane [6, 7] ; Barbuto, Jose Alexandre M. [1] ; Caux, Christophe [2] ; Menetrier-Caux, Christine [2] ; Bendriss-Vermare, Nathalie [2]
Número total de Autores: 18
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil
[2] Univ Claude Bernard Lyon 1, Univ Lyon, Ctr Rech Cancerol Lyon, CNRS 5286, Ctr Leon Berard, INSERM, U1052, F-69008 Lyon - France
[3] Ctr Leon Berard, Lyon - France
[4] Roche Innovat Ctr Munich, Roche Pharmaceut Res & Early Dev, Penzberg - Germany
[5] Perola Byington Hosp, Sao Paulo - Brazil
[6] PSL Res Univ, Inst Curie, Paris - France
[7] INSERM, U932, Paris - France
Número total de Afiliações: 7
Tipo de documento: Artigo Científico
Citações Web of Science: 0

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 (M phi) 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-beta and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163(high)CD86(low)IL-10(high) M2-like M phi 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 M phi (M1-M phi) 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-M phi 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 M phi (M2-M phi) 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. (AU)

Processo FAPESP: 12/13429-2 - Viés supressor de células dendríticas no câncer: investigação em humanos e em modelo murino de possíveis mecanismos
Beneficiário:Rodrigo Nalio Ramos
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
Processo FAPESP: 11/08905-7 - Estudo de mecanismos envolvidos na modulação da resposta de Linfócitos T contra antígenos tumorais por células dendríticas derivadas de monócitos de pacientes com câncer
Beneficiário:Rodrigo Nalio Ramos
Linha de fomento: Bolsas no Brasil - Doutorado