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

Abstract

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 þ 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 þ 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.

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

“…Notably, BRAF V600E PCM and distant metastasis exhibited an increased pDC numbers compared with BRAF-negative [208]. Moreover, we found a significant reduction in pDC density in NRAS + and NF-1 + PCM, particularly when compared with the BRAF + subgroup, whereas no differences were observed in CD8 + T-cell infiltration between TCGA subgroups [206,209]. Furthermore, Batf3-lineage DCs are critical for the induction of anti-tumor CD8 + T cell response.…”

“…However, a reduced pDC density occurs during local progression of PCM. More importantly, we could observe a dramatic decrease in pDC infiltration in distant metastasis ( Figure 4C) combined with a collapse of circulating pDCs in chemo-naïve MM patients [209]. This finding was significant in advanced stage of disease (M1c group), characterized by visceral metastasis or high LDH serum level [209].…”

“…More importantly, we could observe a dramatic decrease in pDC infiltration in distant metastasis ( Figure 4C) combined with a collapse of circulating pDCs in chemo-naïve MM patients [209]. This finding was significant in advanced stage of disease (M1c group), characterized by visceral metastasis or high LDH serum level [209]. The pDC compartment is maintained by progressively restricted bone marrow progenitors [30] and an impairment in the pDC differentiation process might explain the pDC collapse in systemic disease.…”

“…In line with the previous reports [15,261], we have recently documented that pDCs are recruited in the early stages of PCM, particularly at the invasive margin, whereas benign common-type nevi are mostly devoid of pDCs ( Figure 4A). Moreover, we found that blood circulating pDCs efficiently home to draining LNs ( Figure 4B) independently from their metastatic colonization, whereas PCM-infiltrating pDCs represent a non-migratory compartment [209]. However, a reduced pDC density occurs during local progression of PCM.…”

TNF-α inhibitor reduces drug-resistance to anti-PD-1: A mathematical model

“…The number of dendritic cells in advanced melanoma can increase to 400 cells/mm 3 [60]. Taking it to be 200 cells/mm 3 and assuming that the mass of one DC is 5 × 10 −10 g, we get D 0 = 4 × 10…”