Immune Profiling of Uveal Melanoma Liver Metastases and Response to Checkpoint Inhibitors

Responses to immune checkpoint inhibitors (ICIs) differ significantly between uveal melanoma (UM) and cutaneous melanoma (CM) patients. We investigated the immune profile of metastatic UM(mUM) patients and identified markers that are predictive of improved survival. Metastatic liver samples from 189 UM patients and 48 CM patients were analyzed at genomic and transcriptional levels, and survival analysis was performed on a subgroup of 76 ICI-treated mUM patients. UM liver metastases seem to preserve the genomic and immune characteristics of primary UM (pUM), with a low prevalence of ICI markers and high mutation rates of GNA11, GNAQ, BAP1, and SF3B. Compared with mCM, UM liver metastasis showed lower infiltration of several immune cells, but a greater proportion of M2 macrophages. Compared with UM liver metastases, CM liver metastases showed higher expression of G2M checkpoint and EF2 target genes. Among the mUM and mCM samples, expression of G2M and E2F pathway genes was highest in tumors with high TMB values and T-cell inflamed scores. A longer median overall survival (OS) was observed in mUM patients with higher expression of LAG3, HLA class I, or HLA class II; which may represent a small proportion of immune hot tumors. Expression patterns of G2M checkpoint and E2F targets suggest a possible contribution to immunotherapy response.