Abstract
Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an “immune-cold” tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.
Highlights
Recent meta-analysis reviews on progression-free survival (PFS) and overall survival (OS) from different clinical trials have shown that none of the different novel treatments carried out in recent years has improved the prognosis of Uveal melanoma (UM) patients, reinforcing the need for further research
56% of patients had recurred with a median disease-free survival (DFS) of 38.6 months
We have identified a cluster of 213 primary UM samples available in the literature [14,18,19,20,21]
Summary
Monoclonal and combined therapies with anti-programmed death ligand 1 (PDL1) and anticytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors are already a standard therapy for CM These results have not been reproduced in UM [6,7], which differs from CM at the genetic and molecular level and should be treated with specific treatments [8]. A study by Johansson et al analyzing 103 UM by whole-genome sequencing from different sites of the uveal tract demonstrated that only patients with tumors located in the iris showed high TMB. This phenotype is associated with ultraviolet radiation signature, common in CM. We perform a bioinformatics analysis using public gene expression data in order to perform an in-depth characterization of the tumor microenvironment of UM primary tumors and assess its association with prognosis
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