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 2nd; 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; Alex K Shalek

doi:10.1038/s41467-021-25860-5

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

Nat Commun. 2021 Oct 12;12(1):5955. doi: 10.1038/s41467-021-25860-5.

Authors

Sanjay M Prakadan^#^{1

2

3

4

5}, Christopher A Alvarez-Breckenridge^#^{3

6}, Samuel C Markson^#^{3

7}, Albert E Kim^{8

9}, Robert H Klein^{3

7}, Naema Nayyar⁸, Andrew W Navia^{1

2

3

4

5}, Benjamin M Kuter⁸, Kellie E Kolb^{1

2

3

4

5}, Ivanna Bihun⁸, Joana L Mora⁸, Mia Solana Bertalan⁸, Brian Shaw⁸, Michael White⁸, Alexander Kaplan⁸, Jackson H Stocking⁸, Marc H Wadsworth 2nd^{1

2

3

4

5}, Eudocia Q Lee¹⁰, Ugonma Chukwueke¹⁰, Nancy Wang⁹, Megha Subramanian⁸, Denisse Rotem³, Daniel P Cahill⁶, Viktor A Adalsteinsson³, Jeffrey W Miller¹¹, Ryan J Sullivan^{8

9}, Scott L Carter^{12

13

14}, Priscilla K Brastianos^{15

16

17}, Alex K Shalek^{18

19

20

21

22

23

24}

Affiliations

¹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Broad Institute, Harvard University & Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Ragon Institute, Harvard University, Massachusetts Institute of Technology, & Massachusetts General Hospital, Cambridge, MA, USA.
⁶ Department of Neurosurgery, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA.
⁷ Division of Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Medicine, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA.
⁹ Massachusetts General Hospital Cancer Center, Boston, MA, USA.
¹⁰ Division of Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.
¹² Broad Institute, Harvard University & Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹³ Division of Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁴ Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA. [email protected].
¹⁵ Broad Institute, Harvard University & Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹⁶ Department of Medicine, Harvard Medical School & Massachusetts General Hospital, Boston, MA, USA. [email protected].
¹⁷ Massachusetts General Hospital Cancer Center, Boston, MA, USA. [email protected].
¹⁸ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
¹⁹ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
²⁰ Broad Institute, Harvard University & Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
²¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
²² Ragon Institute, Harvard University, Massachusetts Institute of Technology, & Massachusetts General Hospital, Cambridge, MA, USA. [email protected].
²³ Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, USA. [email protected].
²⁴ Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Clinical Trial, Phase II
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized / therapeutic use
Brain Neoplasms / drug therapy*
Brain Neoplasms / immunology
Brain Neoplasms / mortality
Brain Neoplasms / secondary
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / pathology
CTLA-4 Antigen / antagonists & inhibitors
CTLA-4 Antigen / genetics
CTLA-4 Antigen / immunology*
Cell-Free Nucleic Acids / genetics
Cell-Free Nucleic Acids / immunology
Female
Gene Expression Regulation, Neoplastic
Humans
Immune Checkpoint Inhibitors / therapeutic use*
Immunotherapy
Interferon-gamma / genetics
Interferon-gamma / immunology
Ipilimumab / therapeutic use
Male
Meningeal Carcinomatosis / drug therapy*
Meningeal Carcinomatosis / immunology
Meningeal Carcinomatosis / mortality
Meningeal Carcinomatosis / pathology
Meningeal Neoplasms / drug therapy*
Meningeal Neoplasms / immunology
Meningeal Neoplasms / mortality
Meningeal Neoplasms / pathology
Middle Aged
Nivolumab / therapeutic use
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology*
Single-Cell Analysis
Survival Analysis
Tumor Microenvironment / drug effects*
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology

Substances

Antibodies, Monoclonal, Humanized
CTLA-4 Antigen
CTLA4 protein, human
Cell-Free Nucleic Acids
Immune Checkpoint Inhibitors
Ipilimumab
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Nivolumab
Interferon-gamma
pembrolizumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding