Integrated single-cell and transcriptome sequencing analyses develops a metastasis-based risk score system for prognosis and immunotherapy response in uveal melanoma

Abstract

Background: Uveal melanoma (UM) is the most frequent ocular neoplasm with a strong metastatic ability. The prognostic value of metastasis-associated genes (MAGs) of UM remains unclear. It is urgent to develop a prognostic score system according to the MAGs of UM.Methods: Unsupervised clustering was used to identify MAGs-based molecular subtypes. Cox methods were utilized to generate a prognostic score system. The prognostic ability of the score system was detected by plotting ROC and survival curves. The immune activity and underlying function were depicted by CIBERSORT GSEA algorithms.Results: Gene cluster analysis determined two MAGs-based subclusters in UM, which were remarkably different in clinical outcomes. A risk score system containing six MAGs (COL11A1, AREG, TIMP3, ADAM12, PRRX1 and GAS1) was set up. We employed ssGSEA to compare immune activity and immunocyte infiltration between the two risk groups. Notch, JAK/STAT and mTOR pathways were greatly enriched in the high-risk group. Furthermore, we observed that knockdown of AREG could inhibit UM proliferation and metastasis by in vitro assays.Conclusion: The MAGs-based subtype and score system in UM can enhance prognosis assessment, and the core system provides valuable reference for clinical decision-making.

A Comprehensive Pan-cancer Analysis of the Biological Immunomodulatory Function and Clinical Value of CD27

“…On the other hand, this proves that the CD27 activates CD8 + T cell-mediated cellular immunity and improves cancer prognosis 59 , 60 . In particular, CD27 upregulates the JAK-STAT inflammatory pathway in UVM, activating NK cell-mediated cytotoxic pathway 61 . This is related to previous findings that up-regulation to NK cell infiltration in UVM and may lead to UVM-specific adverse prognosis.…”

Heterogeneity and molecular landscape of melanoma: implications for targeted therapy

“…Twenty-one types of immune cells' relative infiltration levels and expression levels of immune checkpoint genes like LAG3, CD276, HAVCR2, PDCD1, CD274, and CTLA4 have been analyzed using bioinformatic tools [132]. There are also some databases and algorithms to assess the potential responsiveness to Immune checkpoint blockers like The Cancer Immunome Atlas (TCIA) and Tumor Immune Dysfunction and Exclusion (TIDE), respectively.…”

Recent Advances in Molecular and Genetic Research on Uveal Melanoma

“…A distinctive signature consisting of nine inflammatory response-related mRNA transcripts (PDE4B, RAF1, CXCL8, P2RX4, LPAR1, ITGA5, CCL24, ITGB3, CCL20) has been correlated with UM survival, highlighting ITGA5 (integrin alpha 5) and P2RX4 (P2X purinoceptor 4) as key mRNA transcripts [ 188 ]. Within the high-risk prognosis group of UM with metastasis-associated genes, there is a notable increase in the activation of antigen-presenting cells (APC) stimulation, checkpoint signaling, HLA (human leukocyte antigen) and type II-IFN (type II interferon) response [ 189 ]. Additionally, four out of the top nine methylation-regulated mRNA transcripts (EDNRB, IL12Rβ2, CALHM2, RNF43) have been associated with immune functions, antitumor activity and UM survival [ 190 ].…”

“…Particularly, IS3 stood out for its favorable prognostic implications and sensitivity to a PD-1 inhibitor, while IS1 was the most immunosuppressive subtype [ 137 , 239 ]. High-risk UMs have been associated with infiltration of specific immunocytes and high expression of particular genes linked to prognosis [ 189 ]. High-risk UM patients exhibit a higher expression of immune checkpoint genes and an enrichment of immune-related markers, indicating potential targets for immunotherapy [ 240 ].…”