BAP1 loss and PRAME expression converge to remodel the tumor-immune ecosystem during uveal melanoma progression
- 1Department of Ophthalmology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
Abstract
Uveal melanoma (UM) is characterized by a small number of recurrent genetic alterations that determine metastatic propensity. BAP1 loss and PRAME expression define the dominant prognostic axes in UM, yet how they promote malignant progression remains unclear. We profiled 190,535 cells from normal uvea, uveal nevus, primary and metastatic UM using single-cell transcriptomics, T cell receptor sequencing, spatial transcriptomics and isogenic perturbation models. Normal melanocytes, nevus cells and UM cells formed a transcriptional continuum marked by loss of differentiation and emergence of neural crest-like, stress-responsive, hypoxic-glycolytic and immune-interacting states. BAP1 loss and PRAME expression imposed distinct but convergent immunoregulatory programs, inducing interferon and TNF-NFkB signaling and MHC-I expression, with HLA-E showing the strongest response. These alterations were accompanied by macrophage and CD8+ T cell remodeling. PRAME-enriched tumor regions formed spatially organized niches enriched for macrophages and plasma cells. These findings define BAP1 loss and PRAME expression as distinct but convergent axes of tumor-immune coevolution and nominate HLA-E as a candidate mediator of immune resistance.
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BibTeX
@misc{dollar2026bap1,
title = {{BAP1 loss and PRAME expression converge to remodel the tumor-immune ecosystem during uveal melanoma progression}},
author = {J. J. Dollar and X. Liu and M. Singh and M. Sorouri and J. N. Kuznetsoff and S. Salazar and A. Cruz and C. L. Decatur and Z. M. Correa and J. W. Harbour},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.752454},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.752454v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - BAP1 loss and PRAME expression converge to remodel the tumor-immune ecosystem during uveal melanoma progression
AU - J. J. Dollar
AU - X. Liu
AU - M. Singh
AU - M. Sorouri
AU - J. N. Kuznetsoff
AU - S. Salazar
AU - A. Cruz
AU - C. L. Decatur
AU - Z. M. Correa
AU - J. W. Harbour
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.752454
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.752454v1
AB - Uveal melanoma (UM) is characterized by a small number of recurrent genetic alterations that determine metastatic propensity. BAP1 loss and PRAME expression define the dominant prognostic axes in UM, yet how they promote malignant progression remains unclear. We profiled 190,535 cells from normal uvea, uveal nevus, primary and metastatic UM using single-cell transcriptomics, T cell receptor sequencing, spatial transcriptomics and isogenic perturbation models. Normal melanocytes, nevus cells and UM cells formed a transcriptional continuum marked by loss of differentiation and emergence of neural crest-like, stress-responsive, hypoxic-glycolytic and immune-interacting states. BAP1 loss and PRAME expression imposed distinct but convergent immunoregulatory programs, inducing interferon and TNF-NFkB signaling and MHC-I expression, with HLA-E showing the strongest response. These alterations were accompanied by macrophage and CD8+ T cell remodeling. PRAME-enriched tumor regions formed spatially organized niches enriched for macrophages and plasma cells. These findings define BAP1 loss and PRAME expression as distinct but convergent axes of tumor-immune coevolution and nominate HLA-E as a candidate mediator of immune resistance.
ER -