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Missing BAP1 Gene Associated with Immunosuppressive Molecules in Uveal Melanoma

By LabMedica International staff writers
Posted on 22 Apr 2020
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Image: Mass cytometry with Helios uses CyTOF technology to enable deep profiling of translational and clinical samples across a range of cell surface and intracellular markers (Photo courtesy of Fluidigm).
Image: Mass cytometry with Helios uses CyTOF technology to enable deep profiling of translational and clinical samples across a range of cell surface and intracellular markers (Photo courtesy of Fluidigm).
Uveal melanoma is a cancer (melanoma) of the eye involving the iris, ciliary body, or choroid (collectively referred to as the uvea). Tumors arise from the pigment cells (melanocytes) that reside within the uvea and give color to the eye.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults, accounting for 5% of all melanomas. Treatment options for primary UM (pUM) include radiotherapy and surgery, and usually achieve excellent local tumor control. Despite this, about 50% of UM patients develop metastatic disease, mainly in the liver.

An international team of oncology scientists led by those at the University of Liverpool (Liverpool, UK) obtained samples of pUM and metastatic UM (mUM) and four fresh enucleated pUMs were included in this study for the analyses. Formalin-fixed paraffin embedded (FFPE) pUM and mUM samples were sectioned at 4 μm thickness and underwent antigen retrieval using the Dako pretreatment module (Agilent Technologies UK Ltd, Stockport, UK). The Maxpar Human Immune Monitoring Panel Kit (Fluidigm, South San Francisco, CA, USA) was used as a reference antibody panel to immune profile primary uveal melanoma tumors.

The four fresh histopathologically‐phenotyped BAP1− pUMs were processed and analyzed using a Fluidigm Helios CyTOF mass cytometer. For RNA immune gene expression analysis, four pUMs, six mUMs, and one normal liver (NL) FFPE samples were used. Only the tumour areas were selected for RNA extraction, or the entire normal liver tissue. Digital spatial profiling analysis of one BAP1− mUM case was performed by NanoString's DSP technology platform to enable digital characterization of protein distributed on the surface of FFPE tissue sections using the Human Immune Oncology panel (NanoString Technologies, Seattle, WA, USA).

The investigators showed that show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA‐DR, CD38, and CD74. Further, single‐cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour‐associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1.

At the protein level, they observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD‐L1, and β‐catenin (CTNNB1), suggesting tumour‐driven immune exclusion and hence the immunotherapy resistance.

Carlos R. Figueiredo, PhD, the lead author of the study from the University of Turku (Turku, Finland) said, “One of the most common genetic alterations that initiates the development of uveal melanoma occurs in a tumor suppressor gene called BAP1. This gene is found absent or mutated in almost 50% of all UM patients and is associated with high-risk of metastasis development, in which immunotherapy will not work.” The study was published in the April 2020 issue of The Journal of Pathology.



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