Vaginal microbiota, genital inflammation, and neoplasia impact immune checkpoint protein profiles in the cervicovaginal microenvironment

Łaniewski, Paweł; Cui, Haiyan; Roe, Denise J.; Chase, Dana M.; Herbst-Kralovetz, Melissa M.

doi:10.1038/s41698-020-0126-x

Cited by 25 publications

(39 citation statements)

References 58 publications

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“…Levels of 73 protein targets were determined in CVL samples using multiplex cytometric bead arrays or enzyme-linked immunosorbent assays and described previously (17, 31, 32). Briefly, protein levels were measured using customized MILLIPLEX MAP® Human Cytokine/Chemokine, Th17, High Sensitivity T Cell, Circulating Cancer Biomarker and Immuno-Oncology Checkpoint Protein Magnetic Bead Panels (Millipore, Billerica, MA) or Human IL-36γ ELISA kit (RayBiotech, Norcross, GA) in accordance with the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Bacterial 16s RNA gene sequence data analyzed in this study were deposited in SRA (PRJNA518153). Immunoproteome and metabolome data are available online as supplementary materials accompanying our previous reports (17, 18, 31, 32).…”

Section: Declarationsmentioning

confidence: 99%

“…These changes are associated with increased risk for adverse gynecologic and reproductive outcomes, including sexually transmitted infection (STI) acquisition (11). Indeed, several clinical studies have demonstrated that HPV infection associates with substantial changes in the cervicovaginal microenvironment, including shifts in microbial (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), metabolic (29,30) and immunoproteomic profiles (17,18,31,32), as well as vaginal pH levels (17), which might drive HPV persistence and/or disease progression.…”

Section: Introductionmentioning

confidence: 99%

“…Yet, the impact of the microbiome on host defenses across cervical carcinogenesis has not been comprehensively studied. Recent studies have revealed that dysbiotic non-Lactobacillus dominant microbiota are associated with elevated levels of pro-inflammatory cytokines, growth and angiogenesis factors, apoptosis-related proteins, and immune checkpoint proteins in the cervicovaginal fluids (17, 31, 32). Another cross-sectional study suggested a link between dysbiotic fusobacteria and immunosuppressive host responses (18).…”

Section: Introductionmentioning

confidence: 99%

“…Here we present an integrated multi-omics analysis of clinical datasets including vaginal microbiome (17), vaginal pH (17), metabolome (29) and immunoproteome (17, 31, 32), which were previously generated using cervicovaginal specimens collected from a cohort ( n =100) of women with cervical cancer, cervical dysplasia, as well as HPV-positive and HPV-negative controls, but which were previously analyzed independently. Cervical cancer disease phenotypes emerge from the interactions between multiple features, including microbial taxa, metabolic activity of microbes, host immune system activity, and the vaginal microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer

Bokulich

Łaniewski

Chase

et al. 2020

Preprint

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Emerging evidence suggests that a complex interplay between human papillomavirus (HPV), microbiota, and the cervicovaginal microenvironment contribute to HPV persistence and carcinogenesis. Integration of multiple omics datasets is predicted to provide unique insight into HPV infection and cervical cancer progression. Cervicovaginal specimens were collected from a cohort (n=100) of Arizonan women with cervical cancer, cervical dysplasia, as well as HPV-positive and HPV-negative controls. Microbiome, immunoproteome and metabolome analyses were performed using 16S rRNA gene sequencing, multiplex cytometric bead arrays, and liquid chromatography-mass spectrometry, respectively. Multi-omics integration methods, including neural networks (mmvec) and Random Forest supervised learning, were utilized to explore potential interactions and develop predictive models. Our integrated bioinformatic analyses revealed that cancer biomarker concentrations were reliably predicted by Random Forest regressors trained on microbiome and metabolome features, suggesting close correspondence between the vaginal microbiome, metabolome, and genital inflammation involved in cervical carcinogenesis. Furthermore, we show that features of the microbiome and host microenvironment, including metabolites, microbial taxa, and immune biomarkers are predictive of genital inflammation status, but only weakly to moderately predictive of cervical cancer state. Different feature classes were important for prediction of different phenotypes. Lipids (e.g. sphingolipids and long-chain unsaturated fatty acids) were strong predictors of genital inflammation, whereas predictions of vaginal microbiota and vaginal pH relied mostly on alterations in amino acid metabolism. Finally, we identified key immune biomarkers associated with the vaginal microbiota composition and vaginal pH (MIF and TNF-alpha), as well as genital inflammation (IL-6, IL-10, leptin and VEGF). Integration of multiple different microbiome "omics" data types resulted in modest increases in classifier performance over classifiers trained on the best performing individual omics data type. However, since the most predictive features cannot be known a priori, a multi-omics approach can still yield insights that might not be possible with a single data type. Additionally, integrating multiple omics datasets provided insight into different features of the cervicovaginal microenvironment and host response. Multi-omics is therefore likely to remain essential for realizing the advances promised by microbiome research.

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Section: Methodsmentioning

confidence: 99%

Section: Declarationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer

Bokulich

Łaniewski

Chase

et al. 2020

Preprint

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Prevotella as the hub of the cervicovaginal microbiota affects the occurrence of persistent human papillomavirus infection and cervical lesions in women of childbearing age via host NF‐κB/C‐myc

Dong

Huang

Cai

et al. 2022

Journal of Medical Virology

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There is evidence that coinfection of cervicovaginal high-risk human papillomavirus (HR-HPV) and bacteria is common in women of childbearing age. However, the relationship between bacterial vaginosis (BV) and persistent HR-HPV infection in women of childbearing age and the underlying mechanisms remain unclear. In this study, we determined whether BV affects persistent HR-HPV infection in women aged 20-45 years and explored the possible mechanisms of their interactions. From January 1 to April 30, 2020, we recruited women aged 20-45 years with and without BV at a ratio of 1:2 from Fujian Maternity and Child Health Hospital. All women were followed up at 0, 12, and 24 months. A BV assay, HR-HPV genotyping and cervical cytology were performed at each follow-up. At 0 months, additional vaginal secretions and cervical exfoliated cells were collected for 16S ribosomal RNA sequencing, bacterial metabolite determination, and POU5F1B, C-myc, TLR4, NF-κB, and hTERT quantification. A total of 920 women were included. The

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Immunometabolic profiling of cervicovaginal lavages identifies key signatures associated with adenomyosis

Lorentzen¹,

Łaniewski²,

Cui³

et al. 2022

iScience

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Vaginal microbiota, genital inflammation, and neoplasia impact immune checkpoint protein profiles in the cervicovaginal microenvironment

Cited by 25 publications

References 58 publications

Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer

Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer

Prevotella as the hub of the cervicovaginal microbiota affects the occurrence of persistent human papillomavirus infection and cervical lesions in women of childbearing age via host NF‐κB/C‐myc

Immunometabolic profiling of cervicovaginal lavages identifies key signatures associated with adenomyosis

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