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Review
. 2022 Jan 27;23(3):1478.
doi: 10.3390/ijms23031478.

New Therapeutic Approaches for Conjunctival Melanoma-What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells

Jennifer Peil  1 , Felix Bock  1   2 , Friedemann Kiefer  3 , Rebecca Schmidt  4 , Ludwig M Heindl  1 , Claus Cursiefen  1   2 , Simona L Schlereth  1   2
Affiliations
Review

New Therapeutic Approaches for Conjunctival Melanoma-What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells

Jennifer Peil et al. Int J Mol Sci. .

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.

Keywords: cDC1; cDC2; conjunctival melanoma; dendritic cells; immunotherapy; lymphatic; pDCs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Clinical picture of CM shows the pigmented tumor overgrowing the limbus and prominent feeder vessels (arrow); (b) Histological picture (Hematoxylin Eosin) of CM: The architecture of the epithelium is destroyed and the basal membrane (broken line) is disrupted by the tumor. Asterisk (*) marks an accumulation of atypical melanocytes characterized by pyknic and basophil cell bodies.
Figure 2
Figure 2
Lymphatic capillaries in mouse dermis. Such high-resolution images of the conjunctiva are not yet available. (A) Maximum intensity projection of wholemount stained mouse dermal lymphatic capillaries. The combination of endothelial-specific (VE-cadherin, PECAM-1) lymph vessel specific (PROX1) and capillary (LYVE1) markers unambiguously identifies lymphatic capillaries. (B–D) Higher magnification depicts the prototypic oak-leaf shape of capillary LECs and the button junctions formed by VE-cadherin, which alternates with LYVE1 and PECAM-1. The colors of the depicted epitopes are indicated on the left. Scale bars (A) 50 µm, (D) 10 µm.
See this image and copyright information in PMC

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