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Updated: Nov 27, 2025
Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma
Published on: January 25, 2015
Comprehensive analysis of cutaneous and uveal melanoma liver metastases
Esmee P Hoefsmit1, Elisa A Rozeman2, Trieu My Van1
1Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Background:
The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB.
Methods:
Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level.
Results:
Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases.
Conclusions:
While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.
Insights
Cutaneous melanoma (CM) and uveal melanoma (UM) show different responses to immune checkpoint blockade (ICB). UM has higher T cell exhaustion, while CM relies more on PD-L1, explaining varied ICB efficacy.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Cutaneous melanoma (CM) and uveal melanoma (UM) exhibit profound disparities in response to immune checkpoint blockade (ICB).
- The underlying mechanisms for this differential response remain poorly understood.
- Comparative analysis of metastases from the same site (liver) is crucial for dissecting these mechanisms.
Purpose of the Study:
- To characterize and compare liver metastases from CM and UM patients.
- To elucidate the molecular and immunological factors contributing to differential ICB response.
- To identify potential therapeutic strategies for improving UM treatment.
Main Methods:
- Genomic analysis (whole exome sequencing) of tumor samples.
- Transcriptional analysis (RNA sequencing) of tumor samples.
- Protein expression analysis (immunohistochemistry, GeoMx Digital Spatial Profiling).
Main Results:
- CM and UM metastases differ in somatic mutation profiles, tumor mutational burden (TMB), and predicted neoantigens.
- UM metastases show higher melanin content and MelanA expression; CM metastases exhibit higher PD-L1 expression.
- Immune infiltration is similar, but UM metastases have a higher ratio of exhausted CD8 T cells.
Conclusions:
- Differential TMB and immune cell exhaustion contribute to varied ICB responses in CM and UM.
- CM's greater dependency on PD-L1 and UM's higher T cell exhaustion explain response differences.
- Reversing T cell exhaustion beyond PD-1 blockade is a potential strategy to improve metastatic UM treatment.
