Uveal melanoma (UM) is a rare and aggressive intraocular malignancy with limited therapeutic options, particularly in the metastatic setting where immune checkpoint inhibitors have demonstrated minimal efficacy. The two most prevalent driver mutations in UM, SF3B1 and BAP1, define molecularly distinct tumor subtypes with divergent clinical trajectories, yet their differential impact on the tumor immune microenvironment remains incompletely characterized. Using publicly available RNA sequencing and clinical data from The Cancer Genome Atlas Uveal Melanoma cohort (TCGA-UVM, n=80), we quantified CD8+ T-cell infiltration scores derived from a five-gene cytotoxic signature (CD8A, CD8B, GZMB, PRF1, IFNG) and compared immune profiles and overall survival between SF3B1-mutant (n=18) and BAP1-mutant (n=12) tumors. BAP1-mutant tumors demonstrated significantly higher CD8+ T-cell infiltration scores compared to SF3B1-mutant tumors (Mann-Whitney U, p=0.0003), despite exhibiting significantly worse overall survival (log-rank p=0.0327). Tumor mutation burden did not differ significantly between groups (p=0.1671) and did not correlate with CD8+ infiltration scores (Spearman r=-0.092, p=0.6277), suggesting that the observed immune differences are independent of mutational load. These findings reveal a paradoxical immune landscape in BAP1-mutant uveal melanoma consistent with potential T-cell exhaustion or active immune suppression, with implications for mutation-stratified immunotherapy selection in this disease.
Ayaan Alinani (Sat,) studied this question.
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