Fig. 4
Driver–TIME functional networks in HNSC subtypes. A Reconstruction of HNSC driver-TIME functional networks. HNSC transcriptional regulatory network was used to identify the transcription factors (TFs) differentially active (DA) in the three HNSC subtypes that correlated with TIME features and were associated with TIME drivers. Combining functional data, the significant functional networks linking these drivers to TIME TFs were derived. B DNMT3B functional subnetwork in HPV+ HNSCs. C Comparison of PHF1 protein activity between DNMT3B-damaged and wild-type (wt) HPV+ HNSCs. D Gene set enrichment analysis (GSEA) plot comparing the activation of the keratinization pathway between DNMT3B-damaged and wt HPV+ HNSCs. E Comparison of DNMT3B-damaged samples between immune (IMU) and keratinization (KRT) HPV+ HNSCs from [72]. F Comparison of FASL gene expression levels between CASP8-damaged and wt HPV− CNAlow HNSCs. G Schematic of cytotoxic T-cell induced apoptosis of cancer cells through the FAS-FASL cascade. H CASP8 functional subnetwork in HPV− CNAlow HNSCs. I Comparison of IRF7 protein activity in CASP8-damaged and wt HPV− CNAlow HNSCs. J GSEA plots comparing the activation of the α/β interferon signalling and apoptosis regulation pathways between CASP8-damaged and wt HPV− CNAlow HNSCs. K GSEA plot comparing the activation of the WNT signalling pathway between TERT-damaged and wt HPV− CNAhigh HNSCs. L TERT functional subnetwork in HPV− CNAhigh HNSCs. M Comparison of PRMT5 protein activity between TERT-damaged and wt HPV− CNAhigh HNSCs. N GSEA plot comparing the activation of the interferon signalling pathway between TERT-damaged and wt HPV− CNAhigh HNSCs. CNA, copy number alteration; HNSC, head and neck squamous cell carcinoma; HPV, human papilloma virus; TIME, tumour immune microenvironment. Distributions (C, F, I, M) were compared using Wilcoxon rank-sum test. Proportions (E) were compared using Fisher’s exact test. GSEAs (D, J, K, N) were performed using gene set permutation tests