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

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, Joana L. Mora, Mia Solana Bertalan, Brian Shaw, Michael White, Alexander Kaplan, Jackson H. Stocking, Marc H. Wadsworth, Eudocia Q. Lee, Ugonma Chukwueke, Nancy Wang, Megha Subramanian, Denisse Rotem, Daniel P. Cahill, Viktor A. Adalsteinsson, Jeffrey W. Miller, Ryan J. Sullivan, Scott L. Carter (), Priscilla K. Brastianos () and Alex K. Shalek ()
Additional contact information
Sanjay M. Prakadan: Massachusetts Institute of Technology
Christopher A. Alvarez-Breckenridge: Harvard University & Massachusetts Institute of Technology
Samuel C. Markson: Harvard University & Massachusetts Institute of Technology
Albert E. Kim: Harvard Medical School & Massachusetts General Hospital
Robert H. Klein: Harvard University & Massachusetts Institute of Technology
Naema Nayyar: Harvard Medical School & Massachusetts General Hospital
Andrew W. Navia: Massachusetts Institute of Technology
Benjamin M. Kuter: Harvard Medical School & Massachusetts General Hospital
Kellie E. Kolb: 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
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
Scott L. Carter: Harvard University & Massachusetts Institute of Technology
Priscilla K. Brastianos: Harvard University & Massachusetts Institute of Technology
Alex K. Shalek: Massachusetts Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25860-5

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