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. Keywords:uveal melanoma, ocular melanoma, immune checkpoint blockade, CTLA-4, cytotoxic T lymphocyte-associated antigen, ipilimumab, PD-1, programmed death 1, pembrolizumab, nivolumab == 1. 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. Keywords:uveal melanoma, ocular melanoma, immune checkpoint blockade, CTLA-4, cytotoxic T lymphocyte-associated antigen, ipilimumab, PD-1, programmed death 1, pembrolizumab, nivolumab == 1. Introduction == 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 also contains blood vessels [1,2], and less frequently from the ciliary body or iris Ametantrone of the eye where melanocytes are also present [3]. With an Ametantrone incidence of 47 cases per million in Europe, it is much rarer than cutaneous melanoma (CM) [4]. Several factors have been associated with an increased risk of developing UM. These include the presence of choroidal or cutaneous nevi [5], fair skin, light eye color [6], oculodermal melanocytosis [7,8], inactivating mutations of the tumor-suppressor BRCA1-associated protein 1 (BAP1) [9,10], and exposure to ultraviolet (UV) radiation [11]. == 1.1. Cutaneous vs. Uveal Melanoma: Genetic Differences and Implications for Prognosis == Although UM and CM both arise from melanocytes and share similar risk factors, these melanoma subtypes substantially differ biologically and clinically [5]. Similar to other cancer entities that Ametantrone Ametantrone 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. About 40% to 50% harbor mutations in theBRAFgene coding for v-Raf murine sarcoma viral oncogene homolog, and about 20% harbor mutations in theNRASgene coding for neuroblastoma rat sarcoma viral oncogene homolog [14,15,16,17]. Both activatingBRAFandNRASmutations lead to a constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway that promotes proliferation and survival, and thereby contribute to cancer formation and progression [18,19]. In contrast to CM, the number of mutations in UM is extremely low [20], and interestingly, typical CM driver mutations are not present in UM and vice versa. Instead ofBRAFandNRASmutations, which are almost never observed in UM [21,22], more than 80% of all UM harbor mutations in the genes encoding the guanine nucleotide-binding proteins Q polypeptide (GNAQ) and 11 (GNA11) [21,22].GNAQand the closely relatedGNA11encode G subunits of heterotrimeric G-proteins that interact with G-protein-coupled receptors. 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 thus a constitutive activation of the PLC/PKC pathway and downstream RAF-MEK-ERK signaling [21,22,25]. Besides, other downstream pathways as Trio-Rho-Rac and YAP-Hippo get activated by mutated G proteins [26]. A high PI3K-Akt-mTOR activity is also frequently observed in UM [27]; however, this seems to be the result of a phosphatase and tensin homolog (PTEN) expression loss [28], rather than due to mutated G proteins [28,29]. Other driver mutations in UM are by far less frequently detected and involveCYSLTR2encoding the G-protein-coupled cysteinyl leukotriene receptor 2 andPLCB4coding for phospholipase C 4, which act immediately upstream and downstream of GNAQ/11 in the signal transduction cascade [20,30,31]. Ametantrone Inactivating mutations inBAP1are present in about 40% to 47% of UM primary tumors and 80% of UM metastases [32]. BAP1 is a tumor suppressor involved in the repair of DNA double strand breaks [33], and about 8% of UM patients carry BAP1 germline mutations leading to a loss of function [34]. Mutations in genes coding for splicing Rabbit Polyclonal to ACOT1 factor 3B, subunit 1 (SF3B1), which is required for RNA splicing, and the eukaryotic translation initiation factor 1A, x-linked (EIF1AX), are present in 29% and 48% [35,36,37], respectively. Commonly observed chromosomal aberrations in primary UM include monosomy of chromosome 3 and loss of chromosome 1p, 6q, and 8p, as well as amplifications of chromosome 1q, 6p, and 8q [38,39,40,41,42]. These alterations also decisively affect the patients prognosis. == 1.2. Uveal Melanoma: Therapy and Prognosis == Several treatment approaches for primary UM are suitable to achieve sufficient control over.