BAP1 loss and PRAME expression converge to remodel the tumor-immune ecosystem during uveal melanoma progression

Uveal melanoma (UM) is a rare form of eye cancer characterized by a handful of recurrent genetic mutations that determine its ability to spread. Two key genetic alterations, BAP1 loss and PRAME expression, are currently the most significant factors in predicting how aggressively UM will progress. However, the exact mechanisms by which these alterations contribute to cancer development and growth are not well understood.

To investigate this, researchers analyzed 190,535 individual cells from different UM stages and surrounding tissues using advanced cellular profiling techniques. Their findings reveal that normal melanocytes, nevus cells, and cancerous UM cells all exist along a shared cellular pathway that is marked by losing specialized functions and adopting stress-induced, hypoxic, and immune-reactive characteristics.

Crucially, the loss of BAP1 and the presence of PRAME trigger separate but complementary reprogramming of the tumor's microenvironment. Both genetic mutations prompt the production of interferon and TNF-NFκB signaling pathways, increase the expression of Major Histocompatibility Complex class I (MHC-I) molecules, and enhance the presence of HLA-E on tumor cells.

These changes collectively orchestrate a shift in the types of immune cells within the tumor, notably attracting macrophages and CD8+ T cells. Furthermore, tumors with higher PRAME levels develop distinct spatial clusters of immune cells, primarily made up of macrophages and plasma cells. The researchers conclude that BAP1 loss and PRAME expression represent two distinct yet interconnected pathways through which UM cells remodel their surroundings to evade the immune system.

Among the potential factors driving this immune resistance, HLA-E emerges as a promising target for future therapeutic interventions.