BAP1 inactivation promotes uveal melanoma metastasis via ITGB2-ICAM axis with retained hypoxia and ECM signatures

Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, the mechanism behind BAP1 deficiency driving UM metastasis is unknown. In this study, we reanalyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations, individual groups showed distinct inter- and intra-tumor heterogeneity. UM with BAP1-MUTs had a greater population of terminally exhausted CD8+ T cells. Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8+ T cells and GDF15hiATF3hiCDKN1hi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, SLC2A1, CAV2, ENO1, PGK1, LOXL2, ITGA5, TGFBI, and VCAN. etc. Together, this study suggested that the ITGB2-ICAM axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures. These findings provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation.