Fig. 1: Hepatic ATF6α activation is prognostic in human HCC.
From: Activated ATF6α is a hepatic tumour driver restricting immunosurveillance
a, Forest plot of the human ATF6α-activation signature in HCC versus non-tumour liver in 22 datasets. CI, confidence interval. b,c, Kaplan–Meier survival curves for TCGA-LIHC patients split by median enrichment of the human ATF6α-activation signature (b) or the Reactome_Unfolded_Protein_Response_UPR (c) MSigDB17 human gene set. d,e, Representative ATF6α IHC identifying ATF6α− or ATF6α+ samples in human HCC TMAs (d) and ATF6α+ tumour grading (e; G1–G3)20. Scale bar, 200 μm (d). f,g, Representative immunoblot (f) and quantification (g) of ATF6α in non-tumour (NT) and tumour (T) lysates from patients with HCC. Vinculin was used as the loading control, run on a cATF6α blot. h, IHC analysis of active (nuclear) and inactive ATF6α in human HCC. Scale bar, 20 µm. i, The percentage of active ATF6α cells in non-tumour liver, tumour margin or tumour centre from patients with HCC. j, Human HCC TMAs with low or high ATF6α expression as determined using IHC (left) were selected for spatial transcriptomics from annotated 300-µm-diameter circular ROIs (right). Scale bars, 400 μm (left) and 100 μm (right). IF, immunofluorescence. k, Principal component analysis (PCA) of spatial transcriptomics with low versus high ATF6α ROIs. l, Ingenuity pathway analysis (IPA) of differentially expressed genes in high versus low ATF6α ROIs. m, t-Distributed stochastic neighbour embedding (t-SNE) plot of liver cell types by IMC in ATF6αlow versus ATF6αhi livers from patients with HCC. n, Representative IMC of ATF6αlow and ATF6αhi HCC. ATF6α (red), E-cadherin (green) and nuclei (blue, left), and CD3+ T cells (green), CD8+ T cells (red) and nuclei (blue, right) are shown. Scale bar, 60 μm. o,p, t-SNE plots of the immune cell distribution (o) and CD8+ T cell subset composition (p) in ATF6αlow and ATF6αhi HCC, as determined using IMC. q, Immune neighbourhood analysis of CD8+, CD8+TCF1+ and CD11c+ cells in ATF6αlow and ATF6αhi HCC. r, ATF6α target gene expression and the human ATF6α-activation signature sorted by response to anti-PD-1 monotherapy25. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Sample sizes, biological replicates and statistical tests are described in the Methods and Source data.
