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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Oct 3

PMID 33008022

Citations 17

Authors

Yamini Krishna

Amelia Acha-Sagredo

Dorota Sabat-Pospiech

Natalie Kipling

Kim Clarke

Carlos R Figueiredo

Helen Kalirai

Sarah E Coupland

Affiliations

Soon will be listed here.

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 , , , , , , 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.

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References

Nemati F, de Montrion C, Lang G, Kraus-Berthier L, Carita G, Sastre-Garau X . Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts. PLoS One. 2014; 9(1):e80836. PMC: 3890263. DOI: 10.1371/journal.pone.0080836. View

Chen C, Zhao S, Karnad A, Freeman J . The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 2018; 11(1):64. PMC: 5946470. DOI: 10.1186/s13045-018-0605-5. View

Damato B, Dopierala J, Coupland S . Genotypic profiling of 452 choroidal melanomas with multiplex ligation-dependent probe amplification. Clin Cancer Res. 2010; 16(24):6083-92. DOI: 10.1158/1078-0432.CCR-10-2076. View

Faiao-Flores F, Emmons M, Durante M, Kinose F, Saha B, Fang B . HDAC Inhibition Enhances the Efficacy of MEK Inhibitor Therapy in Uveal Melanoma. Clin Cancer Res. 2019; 25(18):5686-5701. PMC: 6744978. DOI: 10.1158/1078-0432.CCR-18-3382. View

Coupland S, Thornton S, Kalirai H . Importance of Partial Losses of Chromosome 3 in Uveal Melanoma in the BAP1 Gene Region. JAMA Ophthalmol. 2020; 138(2):188-189. DOI: 10.1001/jamaophthalmol.2019.5491. View

Field M, Decatur C, Kurtenbach S, Gezgin G, van der Velden P, Jager M . PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma. Clin Cancer Res. 2016; 22(5):1234-42. PMC: 4780366. DOI: 10.1158/1078-0432.CCR-15-2071. View

Damato B, Duke C, Coupland S, Hiscott P, Smith P, Campbell I . Cytogenetics of uveal melanoma: a 7-year clinical experience. Ophthalmology. 2007; 114(10):1925-31. DOI: 10.1016/j.ophtha.2007.06.012. View

Gomez D, Wetherill C, Cheong J, Jones L, Marshall E, Damato B . The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection. J Surg Oncol. 2013; 109(6):542-7. DOI: 10.1002/jso.23535. View

Furney S, Pedersen M, Gentien D, Dumont A, Rapinat A, Desjardins L . SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov. 2013; 3(10):1122-1129. PMC: 5321577. DOI: 10.1158/2159-8290.CD-13-0330. View

10.

McCarthy C, Kalirai H, Lake S, Dodson A, Damato B, Coupland S . Insights into genetic alterations of liver metastases from uveal melanoma. Pigment Cell Melanoma Res. 2015; 29(1):60-7. DOI: 10.1111/pcmr.12433. View

11.

Hussain R, Coupland S, Khzouz J, Kalirai H, Parsons J . Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons. Cancers (Basel). 2020; 12(6). PMC: 7352388. DOI: 10.3390/cancers12061388. View

12.

Decaudin D, Dit Leitz E, Nemati F, Tarin M, Naguez A, Zerara M . Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma. Eur J Cancer. 2020; 126:93-103. DOI: 10.1016/j.ejca.2019.12.012. View

13.

Keyse S . Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008; 27(2):253-61. DOI: 10.1007/s10555-008-9123-1. View

14.

Kang X, Li M, Zhu H, Lu X, Miao J, Du S . DUSP4 promotes doxorubicin resistance in gastric cancer through epithelial-mesenchymal transition. Oncotarget. 2017; 8(55):94028-94039. PMC: 5706853. DOI: 10.18632/oncotarget.21522. View

15.

Gupta A, Towers C, Willenbrock F, Brant R, Hodgson D, Sharpe A . Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. Br J Cancer. 2019; 122(4):506-516. PMC: 7028919. DOI: 10.1038/s41416-019-0673-5. View

16.

Figueiredo C, Kalirai H, Sacco J, Azevedo R, Duckworth A, Slupsky J . Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development. J Pathol. 2020; 250(4):420-439. PMC: 7216965. DOI: 10.1002/path.5384. View

17.

Wang J, Jia R, Zhang Y, Xu X, Song X, Zhou Y . The role of Bax and Bcl-2 in gemcitabine-mediated cytotoxicity in uveal melanoma cells. Tumour Biol. 2013; 35(2):1169-75. DOI: 10.1007/s13277-013-1156-6. View

18.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

19.

Damato B, Coupland S . Translating uveal melanoma cytogenetics into clinical care. Arch Ophthalmol. 2009; 127(4):423-9. DOI: 10.1001/archophthalmol.2009.40. View

20.

Mooy C, Luyten G, de Jong P, Luider T, Stijnen T, van de Ham F . Immunohistochemical and prognostic analysis of apoptosis and proliferation in uveal melanoma. Am J Pathol. 1995; 147(4):1097-104. PMC: 1871011. View