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Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis.

ABSTRACT: Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota (VMB). We enrolled women with ICC, high- and low-grade squamous intraepithelial lesions, as well as, HPV-positive and healthy HPV-negative controls. A broad range of cancer biomarkers was present in the local CVM and specifically elevated in ICC patients. The majority of cancer biomarkers were positively correlated to other biomarkers and linked to genital inflammation. Several cancer biomarkers were also negatively correlated to Lactobacillus abundance and positively correlated with abnormal vaginal pH. Finally, a hierarchical clustering analysis of cancer biomarkers and immune mediators revealed three patient clusters, which varied in levels of cancer biomarkers, genital inflammation, vaginal pH and VMB composition. Specific cancer biomarkers discriminated patients with features of the CVM, such as high genital inflammation, elevated vaginal pH and dysbiotic non-Lactobacillus-dominant VMB, that have been associated with HPV persistence, dysplasia and progression to ICC.

SUBMITTER: Laniewski P

PROVIDER: S-EPMC6517407 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis.

Łaniewski Paweł P Cui Haiyan H Roe Denise J DJ Barnes Dominique D Goulder Alison A Monk Bradley J BJ Greenspan David L DL Chase Dana M DM Herbst-Kralovetz Melissa M MM

Scientific reports 20190514 1

Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota ( ...[more]

PMID: 31089160

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Project description:BackgroundImmunotherapy has changed the therapeutic landscape of cervical cancer (CC), but has durable anti-tumor activity only in a subset of patients. This study aims to comprehensively analyze the tumor immune microenvironment (TIME) of CC and to mine biomarkers related to immunotherapy and prognosis.MethodsThe Cancer Genome Atlas (TCGA) data was utilized to identify heterogeneous immune subtypes based on survival-related immune cell signatures (ICSs). ICSs prognostic model was constructed by Cox regression analyses, and immunohistochemistry was conducted to verify the gene with the largest weight coefficient in the model. Meanwhile, the tumor immune infiltration landscape was comprehensively characterized by ESTIMATE, CIBERSORT and MCPcounter algorithms. In addition, we also analyzed the differences in immunotherapy-related biomarkers between high and low-risk groups. IMvigor210 and two gynecologic tumor cohorts were used to validate the reliability and scalability of the Risk score.ResultsA total of 291 TCGA-CC samples were divided into two ICSs clusters with significant differences in immune infiltration landscape and prognosis. ICSs prognostic model was constructed based on eight immune-related genes (IRGs), which showed higher overall survival (OS) rate in the low-risk group (P< 0.001). In the total population, time-dependent receiver operating characteristic (ROC) curves displayed area under the curve (AUC) of 0.870, 0.785 and 0.774 at 1-, 3- and 5-years. Immunohistochemical results showed that the expression of the oncogene (FKBP10) was negatively correlated with the degree of differentiation and positively correlated with tumor stage, while the expression of tumor suppressor genes (S1PR4) was the opposite. In addition, the low-risk group had more favorable immune activation phenotype and higher enrichment of immunotherapy-related biomarkers. The Imvigor210 and two gynecologic tumor cohorts validated a better survival advantage and immune efficacy in the low-risk group.ConclusionThis study comprehensively assessed the TIME of CC and constructed an ICSs prognostic model, which provides an effective tool for predicting patient's prognosis and accurate immunotherapy.

Dataset Information

Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis.

Publications

Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis.

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