Abstract
Conjunctival melanoma (CM) accounts for 5% of all ocular melanomas and arises from malignantly transformed melanocytes in the conjunctival epithelium. Current therapies using surgical excision in combination with chemo- or cryotherapy still have high rates for recurrences and metastatic disease. Lately, novel signal transduction-targeted and immune checkpoint inhibitors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) receptor inhibitors, BRAF- or MEK-inhibitors for systemic treatment of melanoma have improved the outcome even for unresectable cutaneous melanoma, improving patient survival dramatically. The use of these therapies is now also recommended for CM; however, the immunological background of CM is barely known, underlining the need for research to better understand the immunological basics when treating CM patients with immunomodulatory therapies. Immune checkpoint inhibitors activate tumor defense by interrupting inhibitory interactions between tumor cells and T lymphocytes at the so-called checkpoints. The tumor cells exploit these inhibitory targets on T-cells that are usually used by dendritic cells (DCs). DCs are antigen-presenting cells at the forefront of immune response induction. They contribute to immune tolerance and immune defense but in the case of tumor development, immune tolerance is often prevalent. Enhancing the immune response via DCs, interfering with the lymphatic pathways during immune cell migration and tumor development and specifically targeting tumor cells is a major therapeutic opportunity for many tumor entities including CM. This review summarizes the current knowledge on the function of lymphatic vessels in tumor growth and immune cell transport and continues to compare DC subsets in CM with related melanomas, such as cutaneous melanoma and mucosal melanoma.
Highlights
It is important not to consider or treat all melanomas the same. Another completely different ocular melanoma subtype is uveal melanoma. It originates from non-epithelial melanocytes and differs significantly compared to dermal, mucosal and conjunctival melanoma in terms of mutations, with mostly primary mutations located in GNAQ or GNA11, [1,2], which are not of importance in cutaneous melanoma or CM
To natural killer T-cells (NKT), B-cells and mast cells, they found an enrichment of Plasmacytoid Dendritic Cells (pDCs) and activated dendritic cells (DCs) in CM compared to healthy conjunctiva [260]
Despite some similarities with cutaneous melanoma, CM is a mucosal melanoma and only very little is known about immunological responses or DC subsets in CM
Summary
It is important not to consider or treat all melanomas the same Another completely different ocular melanoma subtype is uveal melanoma. It originates from non-epithelial melanocytes and differs significantly compared to dermal, mucosal and conjunctival melanoma in terms of mutations, with mostly primary mutations located in GNAQ or GNA11, [1,2], which are not of importance in cutaneous melanoma or CM. Compared with its closest relatives, cutaneous melanoma and mucosal melanoma, and highlights new therapeutic approaches for the future for all three forms of melanoma. Conjunctiva and mucosa contain several anatomical particularities different from the skin [11], e.g., goblet cells, which produce mucin [12], express transforming growth factor β2 (TGF-β2). TERT mutations are very rare in mucosal melanoma, whereas KIT mutations are the most frequently altered oncogene in mucosal melanomas [21] (different from cutaneous or CM)
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