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Cancer Immunol Res. 2019 Jan;7(1):12-28. doi: 10.1158/2326-6066.CIR-18-0141. Epub 2018 Nov 6.

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome.

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Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Laboratory of Genetic Disorders of Childhood, "Angelo Nocivelli" Institute for Molecular Medicine, Spedali Civili, Brescia, Italy.
Oncology Unit, ASST Spedali Civili di Brescia, Italy.
Pathology Unit, Azienda Romagna, Hospital Santa Maria delle Croci, Ravenna, Italy.
Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
Dermathology Unit, ASST Spedali Civili di Brescia, Italy.
ARC-Net Research Centre and Department of Diagnostics and Public Health, Section of Pathology, Università degli Studi di Verona, Verona, Italy.
Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, ASST Spedali Civili, Brescia, Italy.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.


Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist-based trials.

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