Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Krishna, Yamini, Acha-Sagredo, Amelia, Sabat-Pospiech, Dorota, Kipling, Natalie, Clarke, Kim, Figueiredo, Carlos R, Kalirai, Helen ORCID: 0000-0002-4440-2576 and Coupland, Sarah E ORCID: 0000-0002-1464-2069 (2020) Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma. CANCERS, 12 (10). E2832-.

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Official URL: http://dx.doi.org/10.3390/cancers12102832

Abstract

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 ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p < 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. 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.

Item Type:	Article
Uncontrolled Keywords:	metastatic uveal melanoma, transcriptome profiling, immunotherapy, MUM1, DUSP4
Depositing User:	Symplectic Admin
Date Deposited:	04 Nov 2020 13:24
Last Modified:	18 Jan 2023 23:23
DOI:	10.3390/cancers12102832
Open Access URL:	https://doi.org/10.3390/cancers12102832
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3106034