Loss of BAP1 Expression Is Associated With an Immunosuppressive Microenvironment in Uveal Melanoma, With Implications for Immunotherapy Development.

Abstract

<div><p>Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggest that UM are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune-suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being a regulatory CD8+ T lymphocytes and tumour associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoral fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1 and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1- mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches.</p></div>