Yang Hee Joo, Choi Myoung Eun, Kim Do Hyung, Won Chong Hyun, Chang Sung Eun, Lee Mi Woo, Lee Woo Jin
Dermatology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Dongguk University, Goyang, Korea.
Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
J Eur Acad Dermatol Venereol. 2025 Jun 3. doi: 10.1111/jdv.20780.
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.
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.
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.
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.
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.
肢端黑色素瘤（AM）根据BRAF状态显示出不同的基因组图谱，且缺乏与BRAF和免疫检查点分子相关性的数据。
本研究旨在确定BRAF突变在AM中的意义，根据BRAF状态探索免疫检查点分子的表达模式以及与肿瘤免疫相关的转录组图谱。
对AM组织进行BRAF、程序性死亡蛋白1（PD-1）、淋巴细胞激活基因3（LAG-3）和T细胞免疫球蛋白黏蛋白结构域3（TIM-3）的免疫组织化学（IHC）染色。通过空间转录组分析，检测BRAF表达与免疫检查点分子表达之间的相关性。在mRNA水平上，比较BRAF高表达组和BRAF低表达组，进行差异表达基因分析、通路分析和免疫细胞反卷积分析。
在IHC和空间转录组分析中，BRAF阳性与PD-1、LAG-3和TIM-3的高表达相关。在总共144例患者中，BRAF（p < 0.01）、PD-1（p < 0.01）、LAG-3（p < 0.01）和TIM-3（p < 0.01）的IHC阳性结果与包括病理亚型、细胞形态学、派杰样扩散和巢状形成在内的组织病理学特征显著相关。在空间转录组分析中，LAG-3的表达水平与BRAF的表达水平显著相关（p < 0.01）。BRAF高表达组中与抗肿瘤免疫相关的通路显著下调。在免疫细胞反卷积分析中，BRAF高表达组中的内皮细胞（p = 0.001）、肥大细胞（p = 0.014）和中性粒细胞（p = 0.004）显著增多。
AM中的BRAF突变与免疫检查点分子表达增加相关，支持在临床实践中对BRAF突变型AM使用免疫疗法。BRAF突变型AM中关于肿瘤免疫的不同肿瘤微环境可能解释其预后不良。
