Krishna, Yamini 
ORCID: 0000-0001-5067-3682, 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-.
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 <i>ANXA1</i>, <i>CD74</i>, <i>CXCR4</i>, <i>MIF</i>, <i>STAT3</i>, <i>PLA2G6</i>, and <i>TGFB1</i>. Compared to control liver, mUM showed significant (<i>p</i> < 0.01) upregulation of 10 genes: <i>DUSP4</i>, <i>PRAME</i>, <i>CD44</i>, <i>IRF4/MUM1</i>, <i>BCL2</i>, <i>CD146/MCAM/MUC18</i>, <i>IGF1R</i>, <i>PNMA1</i>, <i>MFGE8/lactadherin</i>, and <i>LGALS3/Galectin-3</i>. 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: | 03 Feb 2024 09:49 |
| DOI: | 10.3390/cancers12102832 |
| Open Access URL: | https://doi.org/10.3390/cancers12102832 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3106034 |
Dimensions
Dimensions
