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

Abstract

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.

Keywords: cutaneous melanoma; immune checkpoint inhibitor; liver metastasis; tumor microenvironment; uveal melanoma.

FIGURE 1

Oncoprint of clinically relevant alterations in 189 UM liver metastases. Blue=altered or high expression. White=wild-type or low expression.

FIGURE 2

Comparison of TME characteristics (quanTIseq) between UM samples and CM samples within liver metastases. The red asterisks in panel A indicate P<0.0001 for lower abundance in the mUM samples compared with the mCM samples. The black asterisks indicate P<0.0001 for greater abundance in mUM compared with mCM.

FIGURE 3

Significant GSEA results for UM samples versus CM samples within liver metastasis. A, GSEA pathways that are enriched in CM liver metastasis compared with UM liver metastasis. B, Z-score distribution of the G2M and E2F pathways for T-cell inflamed values (with combined uveal melanoma and cutaneous melanoma). C, Z-score distribution of the G2M and E2F pathways for TMB values (with combined uveal melanoma and cutaneous melanoma).

FIGURE 4

CODEai analysis for ICI-treated uveal melanoma patients with liver metastasis. A, PD-L1 high versus PD-L1 low. B, PRAME high versus PRAME low. C, LAG3 high versus LAG3 low. D, HLA class II high versus HLA class II low. E, HLA class I high versus HLA class I low.