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Activin A Sustains the Metastatic Phenotype of Tumor-Associated Macrophages and Is a Prognostic Marker in Human Cutaneous Melanoma

  • Alba Gutiérrez-Seijo
    Affiliations
    Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
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  • Elena García-Martínez
    Affiliations
    Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
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  • Celia Barrio-Alonso
    Affiliations
    Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
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  • Verónica Parra-Blanco
    Affiliations
    Servicio de Anatomía Patológica, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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  • José Antonio Avilés-Izquierdo
    Affiliations
    Servicio de Dermatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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  • Author Footnotes
    6 These authors contributed equally to this work.
    Paloma Sánchez-Mateos
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
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  • Author Footnotes
    6 These authors contributed equally to this work.
    Rafael Samaniego
    Correspondence
    Correspondence: Rafael Samaniego, Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón, c/ Maiquez, 9, 28009 Madrid, Spain.
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
    Search for articles by this author
  • Author Footnotes
    6 These authors contributed equally to this work.
Published:September 06, 2021DOI:https://doi.org/10.1016/j.jid.2021.07.179
      Tumor cells attract and dynamically interact with monocytes/macrophages to subvert their differentiation into tumor-associated macrophages (TAMs), which mainly promote immune suppression and neoplastic progression, but the pathways and microenvironmental cues governing their protumoral deviation are not completely understood. To identify the molecular pathways responsible for TAM differentiation, we screened the biomarkers secreted during melanoma‒macrophage interactions using Quantibody microarrays and RNA sequencing of macrophages. We found that activin A, a member of the transforming GF family, plays an instrumental role in the cross-talk between melanoma cells and monocytes/macrophages, which results in the upregulation of distinct tumor-sustaining genes and the achievement of proinvasive and immunosuppressive functions of TAMs. Blockade of activin reduces the upregulation of part of these genes and prevents the acquisition of protumoral functions, facilitating human melanoma rejection by transferred human lymphocytes in a xenograft mouse model. Remarkably, screening of two independent cutaneous primary melanoma collections showed that activin A is enriched in TAMs and melanoma cells from patients with worse outcomes and constitutes a new and independent prognostic marker. Thus, we identify activin A as a key intermediary in the protumoral and immunosuppressive functions of TAMs, with significant potential as a disease biomarker as well as an immunotherapeutic target.

      Abbreviations:

      ACT (adoptive cell transfer), CM (conditioned media), Mo (monocyte), TAM (tumor-associated macrophage), TC (tumor cell)
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