Cellular and Genomic Landscape of Uveal Melanoma at Single Cell Resolution

J. William Harbour, MD

Award Type Established Investigator Award
Institution University of Miami

Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients, with no measurable improvement in survival over the past half century. As such, there is a critical need to develop new therapies for metastatic UM. In contrast to cutaneous melanoma, checkpoint inhibitor immunotherapy is largely ineffective in UM, which is likely due at least in part to the tumor creating an immunosuppressive microenvironment. We hypothesize that the suppressive immune microenvironment in UM is triggered by genomic aberrations that arise during tumor evolution. We propose to address this hypothesis using the latest advances in single-cell DNA and RNA sequencing to study the genomic and immune cell landscape of UM tumors obtained from patients (Aim 1). We will further explore these findings using a novel mouse model of UM developed in our laboratory that will allow us to study the interplay between genomic abnormalities and the host immune system (Aim 2). The overall objective of our research program is to provide the first comprehensive genomic and cellular atlas of UM at single cell resolution. The clinical relevance of the proposal is to stimulate new strategies for effective therapy. This proposal benefits from a unique collaboration between our lab and 10X Genomics to develop and optimize new methods for analyzing mutations in single-cell DNA sequencing data. We also utilize single-nucleus methodology, which can be performed on snap-frozen samples, thereby allowing our large biorepository of annotated samples to be available for analysis. This technology may have clinical applications in the future and provides a critical resource to the scientific community.