Tumour progression shows decrease in PD-L1 expression in matched metastases/primary uveal melanomas.

Area of Science:

• Oncology
• Immunology
• Pathology

Background:

• Immune checkpoint inhibitors (ICI) have transformed cancer treatment but show limited efficacy in metastatic uveal melanoma (UM).
• Understanding the tumor microenvironment in UM is crucial for improving ICI therapy outcomes.

Purpose of the Study:

• To investigate the expression of PD-1, PD-L1, T-cell, and macrophage markers in primary and metastatic UM.
• To elucidate the reasons behind the unsatisfactory response to ICI in metastatic UM.

Main Methods:

• Immunohistochemical (IHC) staining of 32 UM samples (13 primary, 19 metastases) for PD-L1, PD1, CD3, CD4, CD8, CD68, CD163, HLA class I, and BAP1.
• Quantitative and semiquantitative scoring of markers and comparison between primary and metastatic UM, including matched cases.

Main Results:

• Metastatic UM exhibited significantly lower PD-L1 expression on tumor cells compared to primary UM.
• UM metastases showed increased T-cell infiltration (including PD1 expression) but no difference in macrophage infiltration.
• Low HLA Class I expression in metastases correlated with absent PD-L1 and PD1 expression; BAP-1 loss was linked to higher lymphocytic infiltration.

Conclusions:

• Lower PD-L1 expression in UM metastases, despite increased lymphocytic infiltrate, may explain the limited effectiveness of ICI.
• Primary UM might be more responsive to ICI therapy than metastases.
• Targeting primary tumors in a neoadjuvant or adjuvant setting could be beneficial for high-risk patients.