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Here, we established an in vitro three-dimensional (3D) reconstructed organotypic human melanoma-in-skin (Mel-RhS) model to investigate cellular and molecular features of tumor formation over a period of 6\u00a0weeks. Tumor nests developed over time at the epidermal\u2013dermal junction and spread towards the dermis, in places disrupting the basement membrane. This coincided with secretion of matrix metalloproteinase 9 (MMP-9) by melanoma cells. These features resemble the initial stages of invasive melanoma. Interestingly, while the SK-MEL-28 cell line did not secrete detectable levels of interleukin-10 (IL-10) in traditional two-dimensional monolayers, it did express IL-10 in the 3D Mel-RhS, as did the surrounding keratinocytes and fibroblasts. This cellular cross-talk-induced secretion of IL-10 in the Mel-RhS indicated the generation of an immune suppressive microenvironment. Culture supernatants from Mel-RhS interfered with monocyte-to-dendritic-cell differentiation, leading to the development of M2-like macrophages, which was in part prevented by antibody-mediated IL-10 blockade. Indeed, high-dimensional single-cell analysis revealed a shift within the monocyte population away from a CD163<jats:sup>+<\/jats:sup>PD-L1<jats:sup>+<\/jats:sup> M2-like phenotype upon IL-10 blockade. Thus, the 3D configuration of the Mel-RhS model revealed a role for IL-10 in immune escape through misdirected myeloid differentiation, which would have been missed in classical monolayer cultures.<\/jats:p>","DOI":"10.1007\/s00262-020-02626-4","type":"journal-article","created":{"date-parts":[[2020,6,7]],"date-time":"2020-06-07T09:02:36Z","timestamp":1591520556000},"page":"2319-2331","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Micro-environmental cross-talk in an organotypic human melanoma-in-skin model directs M2-like monocyte differentiation via IL-10"],"prefix":"10.1007","volume":"69","author":[{"given":"Elisabetta","family":"Michielon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"L\u00f3pez Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith L. 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Cells resuscitated from the original vial were used up to 23 passages and were cultured for no longer than 6\u00a0months before thawing a new stock vial. The cell line was not re-authenticated but was tested and scored negative for Mycoplasma.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Cell line authentication"}}]}}