Molecular classification of human papillomavirus-positive cervical cancers based on immune signature enrichment

Abstract

BackgroundHuman papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in clinical and molecular characteristics. Thus, an investigation into their heterogeneous immunological profiles is meaningful in providing both biological and clinical insights into this disease.MethodsBased on the enrichment of 29 immune signatures, we discovered immune subtypes of HPV+ cervical cancers by hierarchical clustering. To explore whether this subtyping method is reproducible, we analyzed three bulk and one single cell transcriptomic datasets. We also compared clinical and molecular characteristics between the immune subtypes.ResultsClustering analysis identified two immune subtypes of HPV+ cervical cancers: Immunity-H and Immunity-L, consistent in the four datasets. In comparisons with Immunity-L, Immunity-H displayed stronger immunity, more stromal contents, lower tumor purity, proliferation potential, intratumor heterogeneity and stemness, higher tumor mutation burden, more neoantigens, lower levels of copy number alterations, lower DNA repair activity, as well as better overall survival prognosis. Certain genes, such as MUC17, PCLO, and GOLGB1, showed significantly higher mutation rates in Immunity-L than in Immunity-H. 16 proteins were significantly upregulated in Immunity-H vs. Immunity-L, including Caspase-7, PREX1, Lck, C-Raf, PI3K-p85, Syk, 14-3-3_epsilon, STAT5-α, GATA3, Src_pY416, NDRG1_pT346, Notch1, PDK1_pS241, Bim, NF-kB-p65_pS536, and p53. Pathway analysis identified numerous immune-related pathways more highly enriched in Immunity-H vs. Immunity-L, including cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, antigen processing and presentation, T/B cell receptor signaling, chemokine signaling, supporting the stronger antitumor immunity in Immunity-H vs. Immunity-L.ConclusionHPV+ cervical cancers are divided into two subgroups based on their immune signatures' enrichment. Both subgroups have markedly different tumor immunity, progression phenotypes, genomic features, and clinical outcomes. Our data offer novel perception in the tumor biology as well as clinical implications for HPV+ cervical cancer.

Sequencing-based transcriptome analysis reveals diversification of immune response- and angiogenesis-related expression patterns of early-stage cervical carcinoma as compared with high-grade CIN

“…From pathway enrichment analysis, we found that early stages of invasive CeCa differed from their non-invasive precursor lesions in marked up-regulation of innate immunity pathways, particularly antiviral mechanisms mediated by DNA-sensors, and involvement of IFN-stimulated, pro-inflammatory, as well as DDR-related genes. This probably implies that overstimulation of protective mechanisms in early periods may be one of the triggers and contributors of invasion; at subsequent stages this could become manifest in the form of an immune-active but chronically inflamed and exhausted molecular subtype (43)(44)(45). Relatedness of the DDR-associated processes and "heating-up" the immune TME has also been underscored by some researchers (42,(46)(47)(48).…”

Characteristics of immune-active and immune-silent phenotypes of early-stage cervical carcinoma as revealed by transcriptome sequencing

“…Overstimulation of protective mechanisms in early periods may be one of the triggers and contributors of CeCa invasion. At the same time, at later, advanced stages this could become manifest in the form of a widely documented immune-active but chronically inflamed and exhausted molecular subtype [6,10].…”