Microenvironmental correlates of immune checkpoint inhibitor response in human melanoma brain metastases revealed by T cell receptor and single-cell RNA sequencing
Author:
Alvarez-Breckenridge Christopher A.ORCID, Markson Samuel C.ORCID, Stocking Jackson H., Nayyar Naema, Lastrapes Matthew, Strickland Matthew R., Kim Albert E., de Sauvage Magali, Dahal Ashish, Larson Juliana M, Mora Joana L., Navia Andrew W., Kuter Benjamin M., Gill Corey M.ORCID, Bertalan Mia Solana, Shaw Brian, Kaplan Alexander, Subramanian Megha, Jain Aarushi, Kumar Swaminathan, Danish Husain, White MichaelORCID, Shahid Osmaan, Pauken Kristen E., Miller Brian C., Frederick Dennie T., Herbert Christine, Shaw McKenzie, Martinez-Lage MariaORCID, Frosch Matthew P., Wang Nancy, Gerstner Elizabeth R., Nahed Brian V., Curry William T., Carter Bob S., Cahill Daniel P., Boland Genevieve Marie, Izar BenjaminORCID, Davies Michael, Sharpe Arlene, Suvà Mario L., Sullivan Ryan J., Brastianos Priscilla K.ORCID, Carter Scott L.
Abstract
AbstractMelanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, we collected 32 fresh MBM and performed single cell RNA sequencing of the MBM-TME and T cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe significant relationships between intracranial T cell phenotypes and the distribution of T cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM.
Publisher
Cold Spring Harbor Laboratory
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