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Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases

Author

Listed:
  • Sanjay M. Prakadan

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Harvard University & Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Christopher A. Alvarez-Breckenridge

    (Harvard University & Massachusetts Institute of Technology
    Harvard Medical School & Massachusetts General Hospital)

  • Samuel C. Markson

    (Harvard University & Massachusetts Institute of Technology
    Dana-Farber Cancer Institute)

  • Albert E. Kim

    (Harvard Medical School & Massachusetts General Hospital
    Massachusetts General Hospital Cancer Center)

  • Robert H. Klein

    (Harvard University & Massachusetts Institute of Technology
    Dana-Farber Cancer Institute)

  • Naema Nayyar

    (Harvard Medical School & Massachusetts General Hospital)

  • Andrew W. Navia

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Harvard University & Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Benjamin M. Kuter

    (Harvard Medical School & Massachusetts General Hospital)

  • Kellie E. Kolb

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Harvard University & Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Ivanna Bihun

    (Harvard Medical School & Massachusetts General Hospital)

  • Joana L. Mora

    (Harvard Medical School & Massachusetts General Hospital)

  • Mia Solana Bertalan

    (Harvard Medical School & Massachusetts General Hospital)

  • Brian Shaw

    (Harvard Medical School & Massachusetts General Hospital)

  • Michael White

    (Harvard Medical School & Massachusetts General Hospital)

  • Alexander Kaplan

    (Harvard Medical School & Massachusetts General Hospital)

  • Jackson H. Stocking

    (Harvard Medical School & Massachusetts General Hospital)

  • Marc H. Wadsworth

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Harvard University & Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Eudocia Q. Lee

    (Dana-Farber Cancer Institute)

  • Ugonma Chukwueke

    (Dana-Farber Cancer Institute)

  • Nancy Wang

    (Massachusetts General Hospital Cancer Center)

  • Megha Subramanian

    (Harvard Medical School & Massachusetts General Hospital)

  • Denisse Rotem

    (Harvard University & Massachusetts Institute of Technology)

  • Daniel P. Cahill

    (Harvard Medical School & Massachusetts General Hospital)

  • Viktor A. Adalsteinsson

    (Harvard University & Massachusetts Institute of Technology)

  • Jeffrey W. Miller

    (Harvard TH Chan School of Public Health)

  • Ryan J. Sullivan

    (Harvard Medical School & Massachusetts General Hospital
    Massachusetts General Hospital Cancer Center)

  • Scott L. Carter

    (Harvard University & Massachusetts Institute of Technology
    Dana-Farber Cancer Institute
    Harvard TH Chan School of Public Health)

  • Priscilla K. Brastianos

    (Harvard University & Massachusetts Institute of Technology
    Harvard Medical School & Massachusetts General Hospital
    Massachusetts General Hospital Cancer Center)

  • Alex K. Shalek

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Harvard University & Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.

Suggested Citation

  • Sanjay M. Prakadan & Christopher A. Alvarez-Breckenridge & Samuel C. Markson & Albert E. Kim & Robert H. Klein & Naema Nayyar & Andrew W. Navia & Benjamin M. Kuter & Kellie E. Kolb & Ivanna Bihun & Jo, 2021. "Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25860-5
    DOI: 10.1038/s41467-021-25860-5
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    1. Peter J. Campbell & Shinichi Yachida & Laura J. Mudie & Philip J. Stephens & Erin D. Pleasance & Lucy A. Stebbings & Laura A. Morsberger & Calli Latimer & Stuart McLaren & Meng-Lay Lin & David J. McBr, 2010. "The patterns and dynamics of genomic instability in metastatic pancreatic cancer," Nature, Nature, vol. 467(7319), pages 1109-1113, October.
    2. Alexander C. Huang & Michael A. Postow & Robert J. Orlowski & Rosemarie Mick & Bertram Bengsch & Sasikanth Manne & Wei Xu & Shannon Harmon & Josephine R. Giles & Brandon Wenz & Matthew Adamow & Debora, 2017. "T-cell invigoration to tumour burden ratio associated with anti-PD-1 response," Nature, Nature, vol. 545(7652), pages 60-65, May.
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    Cited by:

    1. Priscilla K. Brastianos & Matthew R. Strickland & Eudocia Quant Lee & Nancy Wang & Justine V. Cohen & Ugonma Chukwueke & Deborah Anne Forst & April Eichler & Beth Overmoyer & Nancy U. Lin & Wendy Y. C, 2021. "Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    2. Amanda Fitzpatrick & Marjan Iravani & Adam Mills & David Vicente & Thanussuyah Alaguthurai & Ioannis Roxanis & Nicholas C. Turner & Syed Haider & Andrew N. J. Tutt & Clare M. Isacke, 2023. "Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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