Head and neck squamous cell carcinomas (HNSCC) promote inflammation in the tumor microenvironment through aberrant NF-κB activation, but the genomic alterations and pathway networks that modulate NF-κB signaling have not been fully dissected. Here, we analyzed genome and transcriptome alterations of 279 HNSCC specimens from The Cancer Genome Atlas (TCGA) cohort and identified 61 genes involved in NF-κB and inflammatory pathways. The top 30 altered genes were distributed across 96% of HNSCC samples, and their expression was often correlated with genomic copy-number alterations (CNA). Ten of the amplified genes were associated with human papilloma virus (HPV) status. We sequenced 15 HPV- and 11 HPV+ human HNSCC cell lines, and three oral mucosa keratinocyte lines, and supervised clustering revealed that 28 of 61 genes exhibit altered expression patterns concordant with HNSCC tissues and distinct signatures related to their HPV status. RNAi screening using an NF-κB reporter line identified 16 genes that are induced by TNFα or Lymphotoxin-β (LTβ) and implicated in the classic and/or alternative NF-κB pathways. Knockdown of TNFR, LTBR, or selected downstream signaling components established cross-talk between the classic and alternative NF-κB pathways. TNFα and LTβ induced differential gene expression involving the NF-κB, IFNγ, and STAT pathways, inflammatory cytokines, and metastasis-related genes. Improved survival was observed in HNSCC patients with elevated gene expression in T-cell activation, immune checkpoints, and IFNγ and STAT pathways. These gene signatures of NF-κB activation, which modulate inflammation and responses to the immune therapy, could serve as potential biomarkers in future clinical trials.

中文翻译：

---

头颈癌通过经典和替代 NF-κB 通路的共激活促进炎症转录组。


头颈鳞状细胞癌 (HNSCC) 通过异常的 NF-κB 激活促进肿瘤微环境中的炎症，但调节 NF-κB 信号传导的基因组改变和通路网络尚未完全剖析。在这里，我们分析了来自癌症基因组图谱 (TCGA) 队列的 279 个 HNSCC 标本的基因组和转录组变化，并鉴定了涉及 NF-κB 和炎症通路的 61 个基因。前 30 个改变的基因分布在 96% 的 HNSCC 样本中，它们的表达通常与基因组拷贝数改变 (CNA) 相关。十个扩增的基因与人乳头瘤病毒（HPV）状态相关。我们对 15 个 HPV- 和 11 个 HPV+ 人类 HNSCC 细胞系以及 3 个口腔粘膜角质形成细胞系进行了测序，监督聚类显示 61 个基因中有 28 个表现出与 HNSCC 组织一致的表达模式改变以及与其 HPV 状态相关的独特特征。使用 NF-κB 报告系进行 RNAi 筛选，鉴定出 16 个由 TNFα 或淋巴毒素-β (LTβ) 诱导且与经典和/或替代 NF-κB 途径有关的基因。 TNFR、LTBR 或选定的下游信号传导成分的敲低在经典和替代 NF-κB 途径之间建立了串扰。 TNFα和LTβ诱导差异基因表达，涉及NF-κB、IFNγ和STAT通路、炎症细胞因子和转移相关基因。在 T 细胞激活、免疫检查点、IFNγ 和 STAT 通路中基因表达升高的 HNSCC 患者中观察到生存率提高。这些 NF-κB 激活的基因特征可以调节炎症和对免疫治疗的反应，可以作为未来临床试验中的潜在生物标志物。