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

  • Biology
  • Cancer
  • Genomics
  • Immunology
  • Medicine
  • Jay Prakadan
  • Andrew Navia
  • Kellie Kolb
  • Marc Wadsworth II
  • Alex K. Shalek
  • Prakadan et al.▾
    Prakadan, S.M., Alvarez-Breckenridge, C.A., Markson, S.C., Kim, A.E., Klein, R.H., Nayyar, N., Navia, A.W., Kuter, B.M., Kolb, K.E., Bihun, I., Mora, J.L., Bertalan, M.S., Shaw, B., White, M., Kaplan, A., Stocking, J.H., Wadsworth II, M.H., Lee, E.Q., Chukwueke, U., Wang, N., Subramanian, M., Rotem, D., Cahill, D.P., Adalsteinsson, V.A., Miller, J.W., Sullivan, R.J., Carter, S.L., Brastianos, P.K., Shalek, A.K.
  • Nature Communications , Volume 12
  • October, 2021
Biology
Cancer
Genomics
Immunology
Medicine
Jay Prakadan
Andrew Navia
Kellie Kolb
Marc Wadsworth II
Alex K. Shalek

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.

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