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

Immune checkpoint inhibitors (ICI) have revolutionised the treatment of several malignancies. However, the results of ICI therapy remain unsatisfactory in metastatic uveal melanoma (UM). We analysed the expression of PD1, PD-L1, T-cell and macrophage markers in a set of matched primary and metastatic UM in an attempt to better understand the low effectiveness of ICI in metastatic UM.

Thirty-two samples (19 metastases and 13 primary UM) were stained for PD-L1, PD1, CD3, CD4, CD8, CD68, CD163, HLA class I and BAP1. T-cell markers were scored quantitatively, while PD-L1, CD68, CD163 and BAP1 were scored semiquantitatively. The immunohistochemical (IHC) scores were compared between all primary and metastatic UM samples and between matched cases.

Both the general and the matched analyses revealed that the IHC scores for PD-L1 expression on tumour cells were lower in metastatic UM than in primary UM. Conversely, T-cell markers, including PD1, were significantly higher in UM metastases than primary UM, while macrophages did not show a difference. Metastases with a low HLA Class I expression lacked PD-L1 and PD1 expression. BAP-1 loss was associated with increased lymphocytic infiltration.

While UM metastases had higher lymphocytic infiltrates than primary UM, PD-L1 showed a lower expression in metastases. We believe that the low effectiveness of ICI in the treatment of metastatic UM may be partly explained by the low PD-L1 expression. We propose that primary tumours may be more responsive to ICI therapy than metastases and could be targeted in a (neo)adjuvant setting for patients at high risk of developing metastases.