TY - JOUR
T1 - Single-cell analysis reveals new evolutionary complexity in uveal melanoma
AU - Durante, Michael A.
AU - Rodriguez, Daniel A.
AU - Kurtenbach, Stefan
AU - Kuznetsov, Jeffim N.
AU - Sanchez, Margaret I.
AU - Decatur, Christina L.
AU - Snyder, Helen
AU - Feun, Lynn G.
AU - Livingstone, Alan S.
AU - Harbour, J. William
N1 - Funding Information:
The authors are grateful to the patients of the senior author (J.W.H.) who generously contributed samples for this research. The authors acknowledge the support of the Biostatistics & Bioinformatics and Oncogenomics Shared Resources at the Sylvester Comprehensive Cancer Center, and the University of Miami Center for Computational Science. The authors thank Dr. Jian-Amadi and Dr. Keene from University of Washington for providing tissue samples and clinical information. This work was supported by National Cancer Institute grant R01 CA125970 (J.W.H.), Research to Prevent Blindness, Inc. Senior Scientific Investigator Award (J.W.H.), Melanoma Research Foundation Established Investigator Award (J.W.H.), the University of Miami Miller School of Medicine Medical Scientist Training Program (M.A.D., D.A.R.), the University of Miami Sheila and David Fuente Graduate Program in Cancer Biology (M.A.D., D.A.R.), the Center for Computational Science Fellowship (M.A.D.), and a generous gift from Dr. Mark J. Daily (J.W.H). The Bascom Palmer Eye Institute received funding from NIH Core Grant P30EY014801 and a Research to Prevent Blindness Unrestricted Grant. The Sylvester Comprehensive Cancer Center also received funding from the National Cancer Institute Core Support Grant P30CA240139.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-14256-1
DO - 10.1038/s41467-019-14256-1
M3 - Article
C2 - 31980621
AN - SCOPUS:85078222023
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 496
ER -