114 CXCL6 emerges as a novel marker of an immunosuppressive, angiogenic, and epithelial-mesenchymal transition (EMT)-enriched metastatic program in uveal melanoma (UM)
Year: 2026
Type: conference-abstract
Abstract: Background Metastatic progression is the major driver of poor outcomes in uveal melanoma (UM), yet the molecular programs supporting metastatic adaptation remain incompletely understood. As CXCL6 is an inflammatory chemokine implicated in angiogenesis, tissue remodeling, and myeloid recruitment, we sought to define the biological and clinical role of CXCL6 expression in metastatic UM.Methods A total of 312 UM tumors (43 eye/local, 269 metastatic) underwent DNA and RNA next generation sequencing at Caris Life Sciences (Phoenix, AZ). Chemokine-related differential expression was compared between BAP1MUT and BAP1WT UM. CXCL6-high tumors were defined as those in the highest quartile of CXCL6 expression (Q4, top 25%), whereas CXCL6-low tumors were defined as those in the lowest quartile (Q1, bottom 25%). Transcriptomic analyses comparing CXCL6-high and low group were performed using ssGSEA in metastatic UM samples. Immune cell fractions were inferred using quanTIseq from RNA-seq. Multiple-testing correction was performed using the Benjamini-Hochberg false discovery rate (FDR) method. Real-world overall survival (OS) was assessed from specimen collection to last clinical contact or death, and time on treatment (TOT) was assessed from initiation to discontinuation of anti–PD-1 therapy based on insurance claims data. Hazard ratios (HR) and p-values were calculated using the Cox proportional hazards and the log-rank test, respectively.Results CXCL6 expression was significantly increased in BAP1MUT compared with BAP1WT metastases (p < 0.01), with no significant difference in primary site. CXCL6-high tumors showed enrichment of angiogenesis, apical surface,epithelial-mesenchymal transition, TGFβ signaling, and hypoxia programs (normalized ssGSEA score difference 0.06–0.18, p < 0.001). Immune deconvolution demonstrated significantly increased M2 macrophages (mean Z-score 0.30 vs. -0.33), and NK-cells (0.47 vs. -0.52), with reduced M1 macrophages abundance (-0.19 vs. 0.17) and myeloid dendritic cells (-0.22 vs. 0.22) in CXCL6-high tumors compared to CXCL6-low tumors (p < 0.05). In the metastatic UM cohort, CXCL6-high group was associated with inferior OS compared with CXCL6-low group (median OS 12.4 vs. 17.2 month, p < 0.005). Among anti–PD-1-treated patients, CXCL6-high showed numerically shorter TOT than CXCL6-low (median 2.3 vs. 4.5 months, p = 0.133).Conclusions CXCL6 identifies an inflammatory transcriptional state in metastatic UM characterized by angiogenic and EMT pathway activation, polarization towards M2 macrophages, and inferior survival. These findings support CXCL6 as a candidate marker of aggressive metastatic remodeling in UM and warrant further validation in independent cohorts and immunotherapy-treated populations.
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225157331