Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors
Lu Sun, … , Won Kim, Robert M. Prins
Lu Sun, … , Won Kim, Robert M. Prins
Published September 1, 2023
Citation Information: J Clin Invest. 2023;133(17):e169314. https://doi.org/10.1172/JCI169314.
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Research Article Immunology Neuroscience

Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors

Abstract

In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB’s effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.

Authors

Lu Sun, Jenny C. Kienzler, Jeremy G. Reynoso, Alexander Lee, Eileen Shiuan, Shanpeng Li, Jiyoon Kim, Lizhong Ding, Amber J. Monteleone, Geoffrey C. Owens, Joanna J. Phillips, Richard G. Everson, David Nathanson, Timothy F. Cloughesy, Gang Li, Linda M. Liau, Willy Hugo, Won Kim, Robert M. Prins

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Figure 1

ICB increases T cell infiltration within the TME of BrM.

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ICB increases T cell infiltration within the TME of BrM. (A) Schematic o...
(A) Schematic of experimental design and analysis workflow. (B) The fraction of tumor-infiltrating T and myeloid cells analyzed with CyTOF (348,257 cells from 37 patients: 8 rGBM, 14 rGBM.ICB, 10 BrM, and 5 BrM.ICB). (C) The number of myeloid and T cells per mg of tissue section from 36 patients: 7 rGBM, 14 rGBM.ICB, 10 BrM, and 5 BrM.ICB. One rGBM sample was excluded because the tumor mass was not recorded. (D) UMAP of tumor-infiltrating CD45+ cells analyzed with scRNA-Seq with 170,129 cells from 53 patients: 11 rGBM, 14 rGBM.ICB, 19 BrM, and 9 BrM.ICB. rGBM and rGBM.ICB data are from Lee et al., 2021, 10 BrM samples are from Gonzalez et al., 2022, and 1 BrM.ICB sample is from Sade-Feldman et al., 2018. (E) The fraction of total TIL and myeloid cells (including the proliferating population) across different tumor groups analyzed by scRNA-Seq. (F) Representative mIF images of immune cell distribution in 33 ICB-naive BrM tumors. Original magnification, ×20. (G) Representative mIF images of immune cell distribution in 5 ICB-treated BrM tumors. Original magnification, ×20. (H) mIF quantification of immune-cell density within the stromal and tumor regions (33 BrM and 5 BrM.I CB). For all box plots, each dot represents a patient, the lower and upper bounds indicate the 25th and 75th percentiles, and the middle lines the median values. P values were calculated using a 2-sided Wilcoxon’s rank-sum test.