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Background <p>Uveal melanoma (UM) is the most common intraocular malignancy, with poor prognosis in metastatic cases and limited response to conventional therapies. Despite advances in genetic stratification, the immunological landscape of primary UM remains poorly understood.</p> Methods <p>Secondary data generation of single-cell RNA sequencing (scRNA-seq) of primary class 1 and class 2 (loss of <i>BAP1</i>) UM tumours and flow cytometric analysis of 8 primary UM tumour biopsies were used to characterize the tumour microenvironment, cellular composition, tumour–immune cell interactions, and stromal marker expression associated with tumour progression and immune infiltration.</p> Results <p>scRNA-seq analysis revealed 16 distinct cell clusters, including melanocytes, T cells, macrophages, and stromal cells. Class 2 tumours contained unique melanocyte subpopulations exhibiting chromosome 8 copy number variations and enriched in hypoxia, PI3K-Akt, and MAPK signalling pathways. Ligand–receptor analysis identified extensive interactions between these aggressive melanocytes and pericytes/macrophages. Flow cytometric analysis confirmed two distinct immune infiltrate profiles: low-infiltrate tumours dominated by CD14⁺ cells, and high-infiltrate tumours with CD8⁺ memory-like T cells expressing PD-1 and CD27. Stromal marker analysis revealed elevated expression of CD81 and NGFR in immune-excluded tumours, implicating them in metastatic potential.</p> Conclusions <p>Our study reveals cellular and immunological heterogeneity within primary UM tumours. The identification of immunologically distinct tumour types, along with aggressive melanocyte subpopulations and stromal interactions, provides insight into UM pathogenesis and supports stratified immunotherapeutic approaches.</p>

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Identification of two distinct uveal melanoma subtypes based on the immune cell infiltration of the primary tumour

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月23日

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  • Konstantinos Panagiotidis,
  • Sally Owens,
  • Grainne Finegan,
  • Noel Horgan,
  • Stefanos Tsavdaridis,
  • Susan Kennedy,
  • Achilleas Floudas

摘要

Background

Uveal melanoma (UM) is the most common intraocular malignancy, with poor prognosis in metastatic cases and limited response to conventional therapies. Despite advances in genetic stratification, the immunological landscape of primary UM remains poorly understood.

Methods

Secondary data generation of single-cell RNA sequencing (scRNA-seq) of primary class 1 and class 2 (loss of BAP1) UM tumours and flow cytometric analysis of 8 primary UM tumour biopsies were used to characterize the tumour microenvironment, cellular composition, tumour–immune cell interactions, and stromal marker expression associated with tumour progression and immune infiltration.

Results

scRNA-seq analysis revealed 16 distinct cell clusters, including melanocytes, T cells, macrophages, and stromal cells. Class 2 tumours contained unique melanocyte subpopulations exhibiting chromosome 8 copy number variations and enriched in hypoxia, PI3K-Akt, and MAPK signalling pathways. Ligand–receptor analysis identified extensive interactions between these aggressive melanocytes and pericytes/macrophages. Flow cytometric analysis confirmed two distinct immune infiltrate profiles: low-infiltrate tumours dominated by CD14⁺ cells, and high-infiltrate tumours with CD8⁺ memory-like T cells expressing PD-1 and CD27. Stromal marker analysis revealed elevated expression of CD81 and NGFR in immune-excluded tumours, implicating them in metastatic potential.

Conclusions

Our study reveals cellular and immunological heterogeneity within primary UM tumours. The identification of immunologically distinct tumour types, along with aggressive melanocyte subpopulations and stromal interactions, provides insight into UM pathogenesis and supports stratified immunotherapeutic approaches.