Extended Data Fig. 10: PD1 and PDL1 targeted immunotherapy in advanced HCC has a distinct effect depending on disease aetiology.
From: NASH limits anti-tumour surveillance in immunotherapy-treated HCC
a, Comparison of RNA-seq data from patients with NASH with varying degrees of fibrosis (F0–F4, Brunt classification) normalized to data from patients with NAFLD from a total of n = 206 patients with NAFLD or NASH. b, c, Immunohistochemical staining (b) and quantification (c) of hepatic PD1+, CD8+, and CD4+ cells from patients with NAFLD or NASH with varying degrees of fibrosis (Supplementary Table 3) (NAFLD n = 9 patients; NASH F0/1 n = 7 patients; NASH F2 n = 12 patients; NASH F3 n = 21 patients; NASH F4 n = 16 patients; CD4: NAFL n = 6 patients; NASH F0/1 n = 4 patients; NASH F2 n = 8 patients; NASH F3 n = 17 patients; NASH F4 n = 9 patients). Scale bar, 100 µm. d, Correlation analysis of PD1 expression against fibrosis grade by immunohistochemical staining (NAFLD/NASH n = 65 patients). e, Immunohistochemical staining and quantification of ratio of PD1+/CD8+ cells in immunohistochemical staining of samples from patient cohort in Supplementary Tables 4–6 (healthy individuals n = 4, NASH n = 26 patients, peri-tumoural NASH–HCC n = 16 patients, peri-tumoural HCC other aetiologies n = 29 patients). Scale bar, 100 µm. f, Immunohistochemical staining and quantification of PD1+ cells and MIB1+ hepatocytes in peri-tumoural and intra-tumoural samples from patients with HCV- or NASH-induced HCC (PD1: peri-tumoural HCV n = 16 tissues from 7 patients; peri-tumoural NASH n = 9 tissues from 2 patients; intra-tumoural HCV n = 10 HCCs from 7 patients; intra-tumoural NASH n = 6 HCCs from 2 patients; MIB1: peri-tumoural HCV n = 16 tissues from 7 patients; peri-tumoural NASH n = 9 tissues from 2 patients; intra-tumoural HCV n = 10 HCCs from 7 patients; intra-tumoural NASH n = 6 HCCs from 2 patients). Arrowheads, PD1+ or MIB1+ cells. Scale bars, 100 μm. g, PRISMA flow chart of the systematic review of targeted immunotherapy in HCC and the selection of articles assessing the clinical outcome of immune checkpoint inhibitors in advanced HCC for inclusion in the systematic review and meta-analysis. ICPI, immune checkpoint inhibitor. A total of 1,243 patients were included in two first-line trials comparing PD1- or PDL1-targeted immunotherapy to sorafenib. In these trials, 707 patients received an immune checkpoint inhibitor (either anti-PD1 or anti-PDL1). h–j, HCV and HBV were pooled into a separate category, termed ‘viral’, and a subsequent meta-analysis comparing viral (n = 754) and non-viral HCC (n = 489; mostly NASH and alcohol intake) was performed (h). A subgroup analysis studying the specific effects of non-viral aetiologies (n = 489) on the magnitude of effect of immunotherapy is presented, when compared to HBV (i; n = 473) or HCV (j; n = 281). HRs for each trial are represented by squares; the size of the square represents the weight of the trial in the meta-analysis. The horizontal line crossing the square represents the 95% CI. The diamonds represent the estimated overall effect based on the meta-analysis random effect of all trials. Inverse variance (IV) and random effects methods (Random) were used to calculate HRs, 95% CIs, P values, and the test for overall effect; these calculations were two-sided. Cochran’s Q-test and I2 were used to calculate heterogeneity. All data are shown as mean ± s.e.m. c, e, f, One-way ANOVA and Dunn’s multiple comparison test. d, Two-tailed Spearman’s correlation.
