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

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.