Figure 2 from PD-1 Blockade–Induced DKK1 Expression by CD8+ T Cells Promotes Blood–Brain Barrier Permeabilization

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Barrier function of the brain is perturbed following anti–PD-1 therapy. A, Scheme illustrating the EB assay performed to evaluate BBB permeability. B, Images of EB-perfused brains harvested from naive (untreated), LPS-, IgG-, and anti-PD-1–treated 8-week-old BALB/c mice (n = 4–6 mice/group). Absorbance of EB dye extracted per gram of brain tissue is plotted. C, Immunofluorescence images showing colocalization of CD31 (blood vessels, red) and EB (green) in the brains of naive (untreated), LPS-, IgG-, and anti-PD-1–treated BALB/c mice. Scale bars, 20 µm. D and E, Eight-week-old BALB/c mice, either non–tumor-bearing or tumor-bearing orthotopic EMT6 breast tumors, were left untreated or treated with IgG or anti–PD-1. Representative DCE-MRI images of mice from different treatment groups are shown (n = 3–4 mice/group; D). Change in gadolinium intensity at 30 minutes after injection is plotted as the ratio of pre-contrast (t = 0, prior to gadolinium injection) to post-contrast signal intensity (E). Arrows indicate regions of increased gadolinium enhancement in the venous sinus area of the anti-PD-1–treated mice. F and G, Immunofluorescence images showing colocalization of CD31 (blood vessels, red) with the tight junction proteins claudin-5 (F, green) and occludin (G, green) in the different treatment groups. The distribution of tight junction proteins along blood vessel surfaces is plotted. Scale bars, 20 µm. H, Scheme illustrating the BrM assay used to assess BrM development as a function of BBB permeability. I, Eight-week-old BALB/c mice were pre-treated with LPS, IgG, anti–PD-1, or left untreated (naive), followed by intracardiac injection of luciferase-tagged EMT6 cells. Mice were then monitored for the development of BrM using bioluminescence imaging. Shown are bioluminescence images of all mice (n = 5 mice/group). The frequency of metastasis in each group is quantified and plotted. J, Representative MRI scans showing brain tumors: In LPS-treated mice, lesions were detected in the corpus callosum and left temporal lobe; in anti-PD-1–treated mice, tumors were localized to the cortical region and the left parasagittal area of the parietal lobe. Arrows indicate the tumor lesions. Significance was assessed using one-way ANOVA for B and E–G and Fisher’s exact test for I (*, P < 0.05; **, P < 0.01; ***, P < 0.001). [A, Created in BioRender. Raviv, Z. (2026) https://BioRender.com/urq64oq; H, Created in BioRender. Raviv, Z. (2026) https://BioRender.com/mqjamit.]

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