Wang Stephanie J, Xiu Joanne, Butcher Katherine M, DeClerck Brittney K, Kim Gene H, Moser Justin, Gibney Geoffrey T, Hernandez-Aya Leonel F, Lutzky Jose, Abdulla Farah, Margolin Kim A, Possik Patrícia Abrão, Robles-Espinoza Carla Daniela, Ito Fumito, In Gino K
Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Caris Life Sciences, Tempe, Arizona, USA.
Pigment Cell Melanoma Res. 2025 May;38(3):e70027. doi: 10.1111/pcmr.70027.
Acral lentiginous melanoma (ALM) is a rare and insufficiently understood subtype of melanoma lacking in effective treatment options. Recent work has demonstrated that the response of ALM to immune checkpoint blockade is inferior to that of cutaneous melanoma (CM). Here we performed bulk genomic and transcriptomic sequencing of tumor tissue from 28 ALM and 5692 CM cases. Similar to prior studies, ALM was associated with a significantly lower incidence of point mutations, including in the TERT promoter and BRAF, but increased numbers of gene amplifications, notably of CCND1, HMGA2, and MDM2. Reactome pathway analysis revealed enhancement of keratinization and PI3K/AKT signaling pathways. Overall immunogenicity was decreased in ALM, which possessed lower IFNγ (p < 0.001) and T-cell inflammatory (p = 0.03) pathway scores than CM. Despite higher computationally inferred levels of myeloid dendritic cells (p = 0.006), neoantigen load independent of predicted HLA binding affinity was lower (p < 0.01) in ALM versus CM. Assessment of classical and nonclassical HLA mRNA levels revealed upregulation of HLA-G, suggesting alternative ALM immune evasion pathways in the setting of lower PD-L1 expression (p = 0.005). Additional research is needed to better understand and therapeutically target signaling networks in the ALM tumor microenvironment.
肢端雀斑样痣黑色素瘤（ALM）是一种罕见且了解不足的黑色素瘤亚型，缺乏有效的治疗选择。最近的研究表明，ALM对免疫检查点阻断的反应不如皮肤黑色素瘤（CM）。在此，我们对28例ALM和5692例CM病例的肿瘤组织进行了大量基因组和转录组测序。与先前的研究相似，ALM与点突变的发生率显著降低相关，包括端粒酶逆转录酶（TERT）启动子和BRAF中的点突变，但基因扩增数量增加，尤其是细胞周期蛋白D1（CCND1）、高迁移率族蛋白A2（HMGA2）和小鼠双微体2（MDM2）。反应组通路分析显示角质化和PI3K/AKT信号通路增强。ALM的整体免疫原性降低，其干扰素γ（IFNγ）（p < 0.001）和T细胞炎症（p = 0.03）通路评分低于CM。尽管计算推断的髓样树突状细胞水平较高（p = 0.006），但与CM相比，ALM中独立于预测的人类白细胞抗原（HLA）结合亲和力的新抗原负荷较低（p < 0.01）。对经典和非经典HLA mRNA水平的评估显示HLA-G上调，提示在程序性死亡受体1配体（PD-L1）表达较低的情况下，ALM存在其他免疫逃逸途径（p = 0.005）。需要进一步的研究来更好地了解ALM肿瘤微环境中的信号网络并将其作为治疗靶点。
