Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women

Melissa M Herbst-Kralovetz,Paweł Łaniewski,Denise J Roe,Haiyan Cui,Dana M Chase,Alison Goulder,Dominique Barnes

doi:10.1038/s41598-018-25879-7

Abstract

While high-risk human papillomavirus (HPV) infection is a well-established risk factor for cervical cancer, there are likely other factors within the local microenvironment that contribute to cervical carcinogenesis. Here we investigated relationships between HPV, vaginal pH, vaginal microbiota (VMB) composition, level of genital immune mediators and severity of cervical neoplasm. We enrolled women with low- and high-grade cervical dysplasia (LGD, HGD), invasive cervical carcinoma (ICC), and healthy controls. HPV16, HPV45, HPV58, and HPV31 were the most prevalent in our cohort with HPV16 and HPV31 genotypes more prevalent in Hispanics. Vaginal pH was associated with ethnicity and severity of cervical neoplasm. Lactobacillus dominance decreased with the severity of cervical neoplasm, which correlated with elevated vaginal pH. Hispanic ethnicity was also associated with decreased Lactobacillus dominance. Furthermore, Sneathia was enriched in all precancerous groups, ICC, abnormal pH and Hispanic origin. Patients with ICC, but not LGD and HGD, exhibited increased genital inflammatory scores and elevated specific immune mediators. Notably, IL-36γ was significantly associated with ICC. Our study revealed local, host immune and microbial signatures associated with cervical carcinogenesis and provides an initial step to understanding the complex interplay between mucosal inflammation, HPV persistence and the VMB.

Highlights

Cervical cancer is the most common human papillomavirus (HPV)-related malignancy with estimated 526,000 new cases and 239,000 deaths worldwide in 20151
Persistent infection with high-risk (HR) HPV genotypes is the primary cause of precancerous cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC), only a small portion of women infected with HPV progress to CIN, and if not treated, to ICC4, suggesting that other factors in the local microenvironment in conjunction with HPV play a role in cancer progression
There was no significant difference among the groups in terms of age (P = 0.64), body mass index (BMI) (P = 0.96), HPV status [including HPV16, HPV18, high-risk (HR) and low-risk (LR) genotypes distribution] (P > 0.05), HPV risk profile (P > 0.10), gravidity (P = 0.25), parity (P = 0.51) or previous loop electrosurgical excision procedure (LEEP) (P = 0.27)

Summary

Introduction

Cervical cancer is the most common human papillomavirus (HPV)-related malignancy with estimated 526,000 new cases and 239,000 deaths worldwide in 20151. We performed a cross-sectional study in Arizona Hispanic and non-Hispanic women to identify associations between HPV genotype distribution, vaginal pH, VMB composition, levels of genital immune mediators, ethnicity and severity of cervical neoplasm. Rates of Lactobacillus-dominant (LD) VMB (defined as ≥80% relative abundance of Lactobacillus spp.) were significantly decreased, whereas dysbiotic non-Lactobacillus-dominant (NLD) VMB were increased in LGD (67%), HGD (56%) and ICC (80%) when compared to Ctrl HPV− (40%) or Ctrl HPV+ (32%) (P = 0.04) (Fig. 3B).

Results

Conclusion