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. 2023 Apr 5;72(9):1758–1773. doi: 10.1136/gutjnl-2022-328364

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© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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Adaptive upregulation of PPARγ correlates with immune dysregulation in mouse models and patients with HCC. (A) ScRNA-seq analysis of tumour cell clusters from Hepa1-6-PD-L1S and PD-L1R tumours with anti-PD-L1 treatment (n=2 per group). UMAP plot of the identified tumour cells. (B) Volcano plot of differentially expressed genes (DEGs; left; Log₂fold-change >0.5 and p<0.05) and KEGG pathway enrichment analysis for top five enriched pathways of DEGs (right; Log₂fold-change>0.5, p<0.05 and normalised expression >0.1) in anti-PD-L1-treated PD-L1S (orange bar) or PD-L1R tumour cells (blue bar), respectively. (C) GSEA plot of PPAR signalling pathway (KEGG) in PD-L1R tumour cells compared with PD-L1S tumour cells. (D) Heatmap showing z-score transformed expression of PPAR-related genes identified in (B) in PD-L1S or PD-L1R tumour cells from each sample. (E) UMAP plots of expression patterns of Ppara (top) and Pparg (bottom) in PD-L1S and PD-L1R single cells. (F) Representative western blot analysis of PPARα and PPARγ in Hepa1-6 or RIL-175-PD-L1S and -PD-L1R cell lines and anti-PD-L1-treated tumour tissues. GAPDH served as loading control. (G) TCGA HCC samples with high (n=55) and low (n=55) mRNA levels of PPARA or PPARG that were stratified by top and bottom 15% in 369 patients were selected for subsequent analysis. GSEA plots of CD8⁺ T cell dysfunction signature in patients with TCGA HCC with high and low expressions of PPARA or PPARG. (H) Kaplan-Meier curves of overall survival in patients with HCC according to the expression of PPARA or PPARG. (I) Prediction of potential clinical ICB response in patients with PPARα^high versus PPARα^low or PPARγ^high versus PPARγ^low HCC using the TIDE signature. (J) Analysis of TIDE, T cell exclusion and MDSC scores by TIDE algorithm in patients with PPARα^high and PPARα^low or PPARγ^high and PPARγ^low HCC. Statistical significance was assessed by two-sided log-rank (Mantel-Cox) test for (H), by two-sided χ² test for (I) and by unpaired two-tailed Student’s t-test for (J). *P<0.05; ***p<0.001; ****p<0.0001. DEGs, differentially expressed genes; GSEA, Gene Set Enrichment Analysis; HCC, hepatocellular carcinoma; ICB, immune-checkpoint blockade; KEGG, Kyoto Encyclopedia of Genes and Genomes; MDSC, myeloid-derived suppressor cell; PD-L1R, programmed death-1-ligand-1 resistant; PD-L1S, programmed death-1-ligand-1 sensitive; PPARγ, peroxisome proliferator-activated receptor-gamma; TIDE, Tumor Immune Dysfunction and Exclusion; UMAP, Uniform Manifold Approximation and Projection.