Immune System Evasion as Hallmark of Melanoma Progression: The Role of Dendritic Cells

Abstract

Melanoma is an immunogenic tumor whose relationship with immune cells resident in the microenvironment significantly influences cancer cell proliferation, progression, and metastasis. During melanomagenesis, both immune and melanoma cells undergo the immunoediting process that includes interconnected phases as elimination, equilibrium, and escape or immune evasion. In this context, dendritic cells (DCs) are active players that indirectly counteract the proliferation of melanoma cells. Moreover, DC maturation, migration, and cross-priming as well as their functional interplay with cytotoxic T-cells through ligands of immune checkpoint receptors result impaired. A number of signals propagated by highly proliferating melanoma cells and accessory cells as T-cells, natural killer cells (NKs), tumor-associated macrophages (TAMs), T-regulatory cells (T-regs), myeloid-derived suppressor cells (MDSCs), and endothelial cells participate to create an immunosuppressive milieu that results engulfed of tolerogenic factors and interleukins (IL) as IL-6 and IL-10. To underline the role of the immune infiltrate in blocking the melanoma progression, it has been described that the composition, density, and distribution of cytotoxic T-cells in the surrounding stroma is predictive of responsiveness to immunotherapy. Here, we review the major mechanisms implicated in melanoma progression, focusing on the role of DCs.

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

“…This is in contrast to other human malignancies, including cutaneous melanoma, where these 3 alternate ICRs are preferentially expressed on tumour cells and are currently in phase I clinical trials [ 53 , 54 , 55 ]. Our results importantly highlight yet again the differences between mUM and metastatic skin melanoma and the urgent need to look for alternate targets and receptors in mUM [ 44 , 45 , 46 , 47 ], which may be specifically found on the tumour cells rather than within the TME, as discussed below.…”

“…As previously described [ 25 , 27 , 28 , 43 ], the predominant lymphocyte population present within most mUM were exhausted CD8+ TILs (82.5%) showing either an “altered excluded” or “altered immunosuppressed” pattern, corresponding to a low or intermediate immunoscore, respectively. Interestingly, those mUM with a “high” TIL immunoscore had upregulation of the CD25/ILR2A , corresponding to regulatory T-cells (Tregs), and thereby creating a TME characterized by immunosuppression directed against tumour antigen-specific effector T cells, B cells, and plasma cells, ultimately leading to immune exhaustion and/or anergy [ 44 , 45 , 46 , 47 ]. Indeed, in this study, very few mUMs contained B-cells and plasma cells.…”

Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients

“…STAT3 is essential for the action of IL-10 and IL-6. IL-6 plays a central role in melanoma development and enhances the IL-10 production via STAT3-dependent signaling [27]. IL-6,10/ JAK-STAT3 pathways are found in many carcinomas, and their hyperactivation was generally related to unfavorable clinical prognosis [28].…”

Impact of anatomic site on antigen-presenting cells in cancer

“…We then discuss known tissue-specific DC and macrophage subsets and their functions in CBT-sensitive carcinomas, such as lung and kidney, as well as CBT-refractive carcinomas, such as breast, ovary, pancreas, and liver. As the contributions of APC to immune responses against melanoma have been recently covered, [23][24][25][26] we focus our review on carcinomas that vary in sensitivity Open access when myeloid APC, sensing various tumor-derived danger signals, infiltrate the tumor microenvironment (TME) and capture tumor antigens. These activated APC then migrate to the draining lymph nodes to prime tumorreactive T cells, and the cycle concludes with T cell infiltration into the tumor and T cell-mediated tumor destruction.…”