Nikitina Anastasiia, Kiriy Daria, Tyshevich Andrey, Tychinin Dmitry, Antysheva Zoya, Sobol Anastasya, Kushnarev Vladimir, Shin Nara, Brown Jessica H, Lewis James, Lang Kuhs Krystle A, Ferris Robert, Wirth Lori, Kotlov Nikita, Faden Daniel L
BostonGene Corp., Waltham, MA 02453, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Viruses. 2024 Dec 24;17(1):4. doi: 10.3390/v17010004.
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HPV-positive HNSCC) has distinct biological characteristics from HPV-negative HNSCC. Using an AI-based analytical platform on meta cohorts, we profiled expression patterns of viral transcripts and HPV viral genome integration, and classified the tumor microenvironment (TME). Unsupervised clustering analysis revealed five distinct and novel TME subtypes across patients (immune-enriched, highly immune and B-cell enriched, fibrotic, immune-desert, and immune-enriched luminal). These TME subtypes were highly correlated with patient prognosis. In order to understand specific factors associated with prognosis, we used the unsupervised clustering of an HPV-positive HNSCC cohort from The Cancer Genome Atlas (TCGA) (n = 53) based on HPV transcript expression, and identified four HPV-related subtypes (E2/E5, E6/E7, E1/E4 and L1/L2). Utilizing both viral transcript and TME subtypes, we found that the E2/E5 HPV subtype was associated with an immune-enriched TME and had a higher overall survival rate compared to other subtypes. The E2/E5 subtype was also enriched for samples without HPV-genome integration, suggesting that the episomal HPV status and E2/E5 expression pattern may be associated with an inflamed microenvironment and improved prognosis. In contrast, E6/E7 subtype samples were associated with the fibrotic and immune-desert TME subtypes, with lower values of T-cell and B-cell gene expression signatures and lower overall survival. Both E1/E4 and L1/L2 subtypes were associated with the immune-enriched luminal subtype. Our results suggest that HPV-transcript expression patterns may drive the modulation of the TME, and thereby impact prognosis.
人乳头瘤病毒（HPV）相关的头颈部鳞状细胞癌（HPV阳性HNSCC）具有与HPV阴性HNSCC不同的生物学特征。我们在meta队列中使用基于人工智能的分析平台，分析了病毒转录本的表达模式和HPV病毒基因组整合情况，并对肿瘤微环境（TME）进行了分类。无监督聚类分析揭示了患者中五种不同的新型TME亚型（免疫富集型、高免疫和B细胞富集型、纤维化型、免疫荒漠型和免疫富集管腔型）。这些TME亚型与患者预后高度相关。为了了解与预后相关的特定因素，我们基于HPV转录本表达，对来自癌症基因组图谱（TCGA）的HPV阳性HNSCC队列（n = 53）进行无监督聚类，确定了四种HPV相关亚型（E2/E5、E6/E7、E1/E4和L1/L2）。利用病毒转录本和TME亚型，我们发现E2/E5 HPV亚型与免疫富集的TME相关，与其他亚型相比总体生存率更高。E2/E5亚型中无HPV基因组整合的样本也更为富集，这表明游离型HPV状态和E2/E5表达模式可能与炎症微环境和预后改善相关。相比之下，E6/E7亚型样本与纤维化和免疫荒漠TME亚型相关，T细胞和B细胞基因表达特征值较低，总体生存率也较低。E1/E4和L1/L2亚型均与免疫富集管腔亚型相关。我们的结果表明，HPV转录本表达模式可能驱动TME的调节，从而影响预后。
