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Single-cell analysis reveals new evolutionary complexity in uveal melanoma

ABSTRACT: Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. In this study we interrogate the tumour microenvironment at single-cell resolution using scRNA-seq of 59,915 tumour and non-neoplastic cells from 8 primary and 3 metastatic samples. A subset analysis of tumour cells confirms the global genomic landscape established from bulk analysis and reveals newly described subclonal genomic complexity and transcriptional states consistent with phenotype plasticity. The immune compartment comprises a previously unrecognized diversity of cell types, including CD8+ T cells expressing the checkpoint marker LAG3, as opposed to PD1 or CTLA4. We identified clonally expanded plasma cells in a rare metastasis from an indolent slow-growing class 1B tumour indicating a role for of antibody-mediated immunity. These findings reveal a dynamic ecosystem in which UM demonstrates new evolutionary complexity. LAG3 is identified as a potential candidate for immune checkpoint blockade in high risk UM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139829 | GEO | 2020/01/24

REPOSITORIES: GEO

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Molecular profiling of driver events in metastatic uveal melanoma

Project description:Uveal melanoma (UM) is a rare form of melanoma with a genetics and immunology that is different from skin melanoma. Previous studies have identified genetic driver events of early stage disease when the tumor is confined to the eye. In this study, we have characterized genomic events in UM metastases using whole-genome and RNA sequencing from thirty-two and twenty-eight patients, respectively, and profiled individual tumor infiltrating lymphocytes in a number of the metastases. We find that 91% of the patients have metastases carrying inactivating events in the tumor suppressor BAP1 and this coincided with somatic alterations in GNAQ, GNA11, CYSLTR2, PLCB4, SF3B1 and/or CDKN2A. Mutational signature analysis revealed a rare subset of tumors with prominent signs of UV damage, associated with outlier mutational burden. We study copy number variations (CNV) and find overrepresented events, some of which were not altered in matched primary eye tumors. A focused siRNA screen identified functionally significant genes of some of the segments recurrently gained. We reintroduced a functional copy of BAP1 into a patient-derived BAP1 deficient tumor cell line and found broad transcriptomic changes of genes associated with subtype distinction and prognosis in primary UM. Lastly, our analysis of the immune microenvironments of metastases revealed a presence of tumor-reactive T cells. However, a large fraction expressed the immune checkpoint receptors such as TIM-3, TIGIT and LAG3. These results provide an updated view of genomic events represented in metastatic UM and immune interactions in advanced lesions.

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2013-11-18 | E-GEOD-51880 | biostudies-arrayexpress

Copy number variation analysis of hepatic metastases from uveal melanoma

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