Abstract
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.
Highlights
Uveal melanoma (UM) represents the most common ocular malignancy in adults
The protein acts as a DNA glycosylase and is involved in the base excision repair mechanism where it initiates the removal of deaminated cytosines and 5-methylcytosines and, in particular, thymine and uracil incorrectly pairing with guanine within CpG dinucleotides [140]
The infiltration of lymphocytes into the tissue is weak, and cell lysis mediated by CD8+ T lymphocytes (CTLs) seems to play a minor role in this process, indicating that immune checkpoint blockade (ICB), which aims to boost the T cell-mediated anti-tumor response, is likely to fail
Summary
Uveal melanoma (UM) represents the most common ocular malignancy in adults. About 85% to 90% of the primary tumors arise from melanocytes residing in the choroid, the pigmented layer of the eyeball that contains blood vessels [1,2], and less frequently from the ciliary body or iris of the eye where melanocytes are present [3]. Similar to other cancer entities that are associated with the exposure to environmental carcinogens such as nonsmall cell lung cancer (NSCLC), CM has an extremely high mutational burden with up to 100 mutations per megabase [12,13] Despite this huge number, a few typical driver mutations are found in the majority of CM tissue samples that affect members of the BRAF-MEK-ERK signaling cascade. In about 90% of all cases, codon 209 [23] located in the Ras-like GTPase domain of the proteins is affected [24], and most commonly, glutamine is substituted by leucine (Q209L) This blocks the GTPase activity of the enzyme, resulting in a constantly bound GTP and a constitutive activation of the PLCβ/PKC pathway and downstream RAF-MEK-ERK signaling [21,22,25].
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