Abstract
Simple SummaryDespite improvements in the early identification and successful control of primary uveal melanoma, 50% of patients will develop metastatic disease with only marginal improvements in survival. This review focuses on the tumor microenvironment and the cross-talk between tumor and immune cells in a tumor characterized by low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. The choice of combining different strategies of immunotherapy remains a feasible and promising option on selected patients.Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunits GNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.
Highlights
An increase in overall response rate (ORR) was observed in combined immune checkpoint blockers (ICB) treatment compared to monotherapy not comparable with the improvement obtained in cutaneous melanoma (CM)
The origin from an immune-privileged site and the development of metastases in the liver, an immune-modulating organ, the low mutational burden, the few neoantigens, and the low expression of PD-L1 on tumor cells contribute to the poor response of Uveal melanoma (UM) to immunotherapy, compared to CM
An increase in ORR was observed in patients receiving combined Ipilimumab and Nivolumab compared to monotherapy
Summary
EIF1AX mutations are not associated with risk of metastasis and show, similar to tumors without BAP1 and SF3B1 mutations, prolonged survival. SF3B1 undergoes metastatic progression later, and tumors with mutated BAP1 metastasize early and rapidly progress with poor survival rates [16]. Many secondary mutations were found by next-generation sequencing to occur in UM patients in the same G-protein-related pathways known as drivers, in particular in the calcium-signaling pathway [9] These secondary driver mutations are likely to affect tumor development and progression. Treatment of primary UM (P-UM) consists in surgery or radiation It has a low local recurrence rate, but almost 50% of the patients develop metastatic disease, prevalently to the liver [1]. Responses will be addressed to define new immune therapeutic strategies for M-UM
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