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Single-cell analysis reveals new evolutionary complexity in uveal melanoma

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  • Michael A. Durante

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Daniel A. Rodriguez

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Stefan Kurtenbach

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Jeffim N. Kuznetsov

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Margaret I. Sanchez

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Christina L. Decatur

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Helen Snyder

    (Cell IDx Inc.)

  • Lynn G. Feun

    (University of Miami Miller School of Medicine)

  • Alan S. Livingstone

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • J. William Harbour

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

Abstract

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8+ T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM.

Suggested Citation

  • Michael A. Durante & Daniel A. Rodriguez & Stefan Kurtenbach & Jeffim N. Kuznetsov & Margaret I. Sanchez & Christina L. Decatur & Helen Snyder & Lynn G. Feun & Alan S. Livingstone & J. William Harbour, 2020. "Single-cell analysis reveals new evolutionary complexity in uveal melanoma," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14256-1
    DOI: 10.1038/s41467-019-14256-1
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    Cited by:

    1. Shravan Leonard-Murali & Chetana Bhaskarla & Ghanshyam S. Yadav & Sudeep K. Maurya & Chenna R. Galiveti & Joshua A. Tobin & Rachel J. Kann & Eishan Ashwat & Patrick S. Murphy & Anish B. Chakka & Visha, 2024. "Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yuan Liu & Jingwen Yang & Tianlu Wang & Mei Luo & Yamei Chen & Chengxuan Chen & Ze’ev Ronai & Yubin Zhou & Eytan Ruppin & Leng Han, 2023. "Expanding PROTACtable genome universe of E3 ligases," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Denise Lau & Sonal Khare & Michelle M. Stein & Prerna Jain & Yinjie Gao & Aicha BenTaieb & Tim A. Rand & Ameen A. Salahudeen & Aly A. Khan, 2022. "Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Jani Huuhtanen & Liang Chen & Emmi Jokinen & Henna Kasanen & Tapio Lönnberg & Anna Kreutzman & Katriina Peltola & Micaela Hernberg & Chunlin Wang & Cassian Yee & Harri Lähdesmäki & Mark M. Davis & Sat, 2022. "Evolution and modulation of antigen-specific T cell responses in melanoma patients," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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