Krishna Yamini, Acha-Sagredo Amelia, Sabat-Pośpiech Dorota, Kipling Natalie, Clarke Kim, Figueiredo Carlos R, Kalirai Helen, Coupland Sarah E
Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Foundation Trust, Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
Liverpool Ocular Oncology Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, William Henry Duncan Building, West Derby Street, Liverpool L7 8TX, UK.
Cancers (Basel). 2020 Sep 30;12(10):2832. doi: 10.3390/cancers12102832.
Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an "immunoscore" (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver; intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of , , , , , , and . Compared to control liver, mUM showed significant ( < 0.01) upregulation of 10 genes: , , , , , , , , , and . Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases; LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions.
转移性葡萄膜黑色素瘤（mUM）至肝脏是无法治愈的。对40例福尔马林固定石蜡包埋的mUM肝切除术标本和6例对照肝脏标本进行了转录组分析。使用针对肿瘤浸润淋巴细胞（TILs）和巨噬细胞（TAMs）的“免疫评分”（缺失/改变/高）对mUM进行形态学、核BAP1（nBAP1）表达及其肿瘤微环境（TME）评估。比较了mUM与对照肝脏之间的转录组；还进行了节段间和肿瘤内分析。大多数mUM为上皮样细胞类型（75%）、无色素性（55%）和nBAP1阴性（70%）。它们的TIL免疫评分为中等（68%）或缺失（15%），TAM免疫评分为中等（53%）或高（45%）。M2-TAMs在mUM-TME中占主导， 、 、 、 、 、 和 的表达上调。与对照肝脏相比，mUM显示10个基因显著（<0.01）上调： 、 、 、 、 、 、 、 、 和 。DUSP4、CD44、IRF4、BCL-2、CD146和IGF1R的蛋白表达在所有mUM中均得到验证，而PRAME的蛋白表达在10%的病例中得到验证；LGALS3染色TAMs，而MFGEF8仅突出胆管。节段间的mUM显示出不同的转录组，而单个mUM内的转录组相似。我们的结果表明，M2-TAMs在mUM-TME中占主导，导致免疫抑制的基因上调。mUM显著过表达具有可靶向信号通路的基因，但这些基因在节段间病变中可能有所不同。
