Human Melanoma-Associated Mast Cells Display a Distinct Transcriptional Signature Characterized by an Upregulation of the Complement Component 3 That Correlates With Poor Prognosis

Abstract

Cutaneous melanoma is one of the most aggressive human malignancies and shows increasing incidence. Mast cells (MCs), long-lived tissue-resident cells that are particularly abundant in human skin where they regulate both innate and adaptive immunity, are associated with melanoma stroma (MAMCs). Thus, MAMCs could impact melanoma development, progression, and metastasis by secreting proteases, pro-angiogenic factors, and both pro-inflammatory and immuno-inhibitory mediators. To interrogate the as-yet poorly characterized role of human MAMCs, we have purified MCs from melanoma skin biopsies and performed RNA-seq analysis. Here, we demonstrate that MAMCs display a unique transcriptome signature defined by the downregulation of the FcεRI signaling pathway, a distinct expression pattern of proteases and pro-angiogenic factors, and a profound upregulation of complement component C3. Furthermore, in melanoma tissue, we observe a significantly increased number of C3+ MCs in stage IV melanoma. Moreover, in patients, C3 expression significantly correlates with the MC-specific marker TPSAB1, and the high expression of both markers is linked with poorer melanoma survival. In vitro, we show that melanoma cell supernatants and tumor microenvironment (TME) mediators such as TGF-β, IL-33, and IL-1β induce some of the changes found in MAMCs and significantly modulate C3 expression and activity in MCs. Taken together, these data suggest that melanoma-secreted cytokines such as TGF-β and IL-1β contribute to the melanoma microenvironment by upregulating C3 expression in MAMCs, thus inducing an MC phenotype switch that negatively impacts melanoma prognosis.

Mast cell chymase is in contact with melanoma cells in vivo and it detaches melanoma cells from the substratum in vitro

“…Mast cells may be immunoregulatory by affecting complement C3-related pathology, as suggested in basal cell carcinoma [reviewed in ( 7 )]. Recently, melanoma-secreted TGF-b and IL-1b were shown to upregulate C3 expression in melanoma-associated mast cells ( 40 ). Interestingly, chymase controls C3 effects by degrading C3, which has been reported in cutaneous vasculitis ( 27 ).…”

Mast Cells as a Target—A Comprehensive Review of Recent Therapeutic Approaches

“…A similar association, though controversial, has been reported for breast [ 75 , 88 , 89 , 90 , 91 , 92 ], lung [ 93 , 94 , 95 ], and prostate cancer [ 96 , 97 ]. Furthermore, recent studies showed that human melanoma-associated Mast Cells characterized by an upregulation of the complement component C 3 correlates with poor prognosis [ 98 ].…”

Melanomas and mast cells: an ambiguous relationship

“…As highlighted in recent reviews, the role of MCs in tumor development and progression is less straightforward and depends on tumor type and stage [4][5][6]. MCs accumulate in non-hematopoietic cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma, and melanoma [7,8]. Given the highly variable roles of MCs in different types of tumors, this review is focused specifically on the role of MCs in melanoma.…”

“…Numerous studies have sought to define roles for MCs in melanoma progression with conflicting results, depending on the parameters of MC activation evaluated, the stage of melanoma and the model utilized to investigate MC function. Transcriptome and predictive modeling studies link intratumoral MCs with poor prognosis, metastasis, and resistance to co-stimulatory blockade [7,[12][13][14][15][16][17]. Reduced metastasis has consistently been reported in mouse models in which melanomas are intravenously transplanted into mice fully deficient in MCs (Kit Wsh/Wsh ), or mice in which connective tissue type MCs are constitutively or transiently depleted [18][19][20].…”

“…Melanoma-derived MCs have a unique gene signature compared with normal MCs or MCs isolated from basal cell carcinomas [7]. MCs from melanomas have decreased expression of FcεRI-signaling genes, but increased expression of complement (C3)-pathway genes.…”