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

Yamini Krishna,Natalie Kipling,Amelia Acha-Sagredo,Helen Kalirai,Kim Clarke,Dorota Sabat-Pośpiech,Carlos R Figueiredo,Sarah E Coupland

doi:10.3390/cancers12102832

Yamini Krishna, Natalie Kipling + Show 6 more

Open Access

https://doi.org/10.3390/cancers12102832

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Journal: Cancers	Publication Date: Sep 30, 2020
Citations: 30	License type: CC BY 4.0

Affiliation: University of Liverpool, University of Turku

Abstract

Simple SummaryUveal melanoma (UM) is a rare aggressive eye cancer. Although treatment of the eye tumour is successful, about 50% of UM patients develop a relapse of their cancer in the liver. At present, such advanced disease is not curable. A better understanding of the metastatic UM (mUM) in the liver is essential to improve patient survival. This study examines both the response of immune cells within the liver to the UM secondaries (metastases), as well as the expression of various proteins by the UM cells. Our study demonstrates that there is a limited immune response to the mUM, but reveals that a certain type of reactive immune cell: a protumourigenic subset of macrophage is dominant within the mUM. Our research also reveals novel proteins within the mUM, which are specific to these cells and therefore may be targetable in future therapies.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.

Highlights

Uveal melanoma (UM) is an aggressive primary intraocular malignancy with ~50% of UM patients developing metastatic disease, usually in the liver, during the first decade after primary treatment [1,2,3,4,5].UM is distinct from skin melanoma and characterized by certain genetic alterations that are unique to this tumour [1,2,6,7,8,9,10]
We reveal the expression of novel markers, which are specific to Metastatic uveal melanoma (mUM) and thereby may be the focus of targeted therapy
Pathological, and genetic data for a smaller cohort of the mUM cases have been previously published by our group [25,29]

Summary

Introduction

Uveal melanoma (UM) is an aggressive primary intraocular malignancy with ~50% of UM patients developing metastatic disease, usually in the liver, during the first decade after primary treatment [1,2,3,4,5].UM is distinct from skin melanoma and characterized by certain genetic alterations that are unique to this tumour [1,2,6,7,8,9,10]. Uveal melanoma (UM) is an aggressive primary intraocular malignancy with ~50% of UM patients developing metastatic disease, usually in the liver, during the first decade after primary treatment [1,2,3,4,5]. Current treatments for metastatic UM (mUM) to the liver include metastasectomy, liver lobe resection, systemic chemotherapy, or isolated liver perfusion, as well as radiofrequency ablation. None of these therapies are curative [2,4,20,21]. There is an urgent need to improve current treatments for established mUM and to develop neoadjuvant therapies when mUM tumour volumes are low or even clinically imperceptible [22]

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