Immune checkpoint molecules and spatial transcriptome profiles according to BRAF status in acral melanoma

Abstract

Background: Acral melanoma (AM) shows different genomic profiles based on BRAF status, and the data on the association with BRAF and immune checkpoint molecules are lacking. Objectives: This study aimed to identify the significance of BRAF mutation in AMs, exploring expression patterns of immune checkpoint molecules and transcriptome profiles related to tumour immunity according to BRAF status. Methods: Immunohistochemical (IHC) staining of BRAF, Programmed death-1 (PD-1), Lymphocyte-activation gene-3 (LAG-3) and T-Cell Immunoglobulin and mucin domain-3 (TIM-3) was performed on AM tissues. Through spatial transcriptome analysis, the correlation between BRAF expression and immune checkpoint molecule expression was examined. Analysis on differentially expressed genes along with pathway analysis and immune cell deconvolution was performed comparing BRAF-high and BRAF-low groups at the mRNA level. Results: In IHC and spatial transcriptome analysis, BRAF positivity was associated with high expression of PD-1, LAG-3 and TIM-3. Among a total of 144 patients, positive IHC results for BRAF (p < 0.01), PD-1 (p < 0.01), LAG-3 (p < 0.01) and TIM-3 (p < 0.01) were significantly associated with histopathologic traits including pathological subtypes, cytomorphology, pagetoid spread and nest formation. In spatial transcriptome analysis, the expression level of LAG-3 showed a significant association with the expression level of BRAF (p < 0.01). Pathways related to anti-tumour immunity were significantly downregulated in the BRAF-high group. In immune cell deconvolution, endothelial cells (p = 0.001), mast cells (p = 0.014) and neutrophils (p = 0.004) were significantly higher in the BRAF-high group. Conclusions: BRAF mutation in AM is associated with increased expression of immune checkpoint molecules, supporting the use of immunotherapy for BRAF-mutant AM in clinical practice. Different tumour microenvironments regarding tumour immunity in BRAF-mutant AM may explain the poor prognosis.