Activities per year
Abstract
Preclinical assessment of novel therapies to fight cancer requires models that reflect the human physiology and immune response. 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 weeks. Tumor nests developed over time at the epidermal–dermal 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+PD-L1+ 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.
Original language | English |
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Pages (from-to) | 2319-2331 |
Number of pages | 13 |
Journal | Cancer Immunology, Immunotherapy |
Volume | 69 |
Issue number | 11 |
DOIs | |
Publication status | Published - 1 Nov 2020 |
Keywords
- IL-10
- M2 macrophages
- Melanoma
- Reconstructed human skin
- Tumor microenvironment
- Tumor progression
Activities
- 1 Oral presentation
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Immunosuppressive microenvironment of organotypic human melanoma-in-skin model directs monocyte differentiation into M2-like phenotype via IL-10
Elisabetta Michielon (Speaker)
30 Jan 2020Activity: Lecture / Presentation › Oral presentation › Academic