Melissa M Herbst-Kralovetz

Immunometabolic Contributions of Atopobiaceae Family Members in Human Papillomavirus Infection, Cervical Dysplasia, and Cancer

Abstract Background In the cervicovaginal environment, human papillomavirus (HPV) acquisition and cervical cancer progression are linked to non-Lactobacillus dominance, of which Atopobiaceae are key taxa. We hypothesize that Atopobiaceae modulates the cervicovaginal microenvironment to promote HPV persistence and progression to cancer. However, the extent to which Atopobiaceae impact the immunometabolic microenvironment is poorly understood. Methods We investigated Atopobiaceae in a cohort of primarily Hispanic and non-Hispanic White women who were HPV-negative (n = 20), HPV-positive (n = 31) without dysplasia, diagnosed with cervical dysplasia (n = 38), or newly diagnosed with invasive cervical carcinoma (n = 9). Microbiome data were integrated with clinical and demographic surveys, immunoproteomics, and metabolomics data. Results Atopobiaceae identified were Fannyhessea vaginae, Fannyhessea massiliense, Fannyhessea species type 2, Lancefieldella deltae, and an unclassified species. A higher prevalence of Atopobiaceae was observed in women who were Hispanic and had higher gravidity and parity. F. species type 2 and F. vaginae were observed with infections of high-risk HPV genotypes 31 and 52. Atopobiaceae were negatively correlated with Lactobacillus and positively correlated to Sneathia, Dialister, Anaerococcus, Prevotella, and Bifidobacterium/Gardnerella. Proinflammatory cytokines (IL-1α, IL-1β, IL-12, TNF-α), immune checkpoint proteins (PD-L1, LAG3), and cancer biomarkers (CEA, MIF, TRAIL) were positively associated with Atopobiaceae-rich profiles. Prooncogenic metabolites, including 4-hydroxybutyrate and sphingosine, were also elevated in women colonized by Atopobiaceae. Conclusions Our data implicate Atopobiaceae in lipid modulation, oxidative stress, inflammatory responses, and immune evasion, which may contribute to cancer. This study highlights a key family of pathogenic cervicovaginal bacteria that could be exploited to monitor HPV persistence and/or targeted to prevent HPV-mediated cancer.

The Vaginal Microbiota, Human Papillomavirus Infection, and Cervical Carcinogenesis: A Systematic Review in the Latina Population

Abstract Background Latina women experience disproportionately higher rates of HPV infection, persistence, and progression to cervical dysplasia and cancer compared to other racial–ethnic groups. This systematic review explores the relationship between the cervicovaginal microbiome and human papillomavirus infection, cervical dysplasia, and cervical cancer in Latinas. Methods The review abides by the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, EMBASE, and Scopus databases were searched from January 2000 through November 11, 2022. The review included observational studies reporting on the cervicovaginal microbiota in premenopausal Latina women with human papillomavirus infection, cervical dysplasia, and cervical cancer. Results Twenty-five articles were eligible for final inclusion (N = 131,183). Forty-two unique bacteria were reported in the cervicovaginal microbiome of Latinas. Seven bacteria: Lactobacillus crispatus, Lactobacillus iners, Chlamydia trachomatis, Prevotella spp., Prevotella amnii, Fusobacterium spp. and Sneathia spp. were enriched across multiple stages of cervical carcinogenesis in Latinas. Therefore, the total number of reported bacteria includes four bacteria associated with the healthy state, 16 bacteria enriched in human papillomavirus outcomes, 24 unique bacteria associated with abnormal cytology/dysplasia, and five bacteria associated with cervical cancer. Furthermore, three studies reported significantly higher alpha and beta diversity in Latinas with cervical dysplasia and cancer compared to controls. Lactobacillus depletion and an increased abundance of L. iners in Latinas compared to non-Latinas, regardless of human papillomavirus status or lesions, were observed. Conclusions The identification of 42 unique bacteria and their enrichment in cervical carcinogenesis can guide future cervicovaginal microbiome research to better inform cervical cancer prevention strategies in Latinas.

Designing Inclusive HPV Cancer Vaccines and Increasing Uptake among Native Americans—A Cultural Perspective Review

Despite a global and nationwide decrease, Native Americans continue to experience high rates of cancer morbidity and mortality. Vaccination is one approach to decrease cancer incidence such as the case of cervical cancer. However, the availability of vaccines does not guarantee uptake, as evident in the Coronavirus 2019 pandemic. Therefore, as we consider current and future cancer vaccines, there are certain considerations to be mindful of to increase uptake among Native Americans such as the incidence of disease, social determinants of health, vaccine hesitancy, and historical exclusion in clinical trials. This paper primarily focuses on human papillomavirus (HPV) and potential vaccines for Native Americans. However, we also aim to inform researchers on factors that influence Native American choices surrounding vaccination and interventions including cancer therapies. We begin by providing an overview of the historical distrust and trauma Native Americans experience, both past and present. In addition, we offer guidance and considerations when engaging with sovereign Tribal Nations in vaccine development and clinical trials in order to increase trust and encourage vaccine uptake.

Novel Vaccine Strategies and Factors to Consider in Addressing Health Disparities of HPV Infection and Cervical Cancer Development among Native American Women

Cervical cancer is the 4th most common type of cancer in women world-wide. Many factors play a role in cervical cancer development/progression that include genetics, social behaviors, social determinants of health, and even the microbiome. The prevalence of HPV infections and cervical cancer is high and often understudied among Native American communities. While effective HPV vaccines exist, less than 60% of 13- to 17-year-olds in the general population are up to date on their HPV vaccination as of 2020. Vaccination rates are higher among Native American adolescents, approximately 85% for females and 60% for males in the same age group. Unfortunately, the burden of cervical cancer remains high in many Native American populations. In this paper, we will discuss HPV infection, vaccination and the cervicovaginal microbiome with a Native American perspective. We will also provide insight into new strategies for developing novel methods and therapeutics to prevent HPV infections and limit HPV persistence and progression to cervical cancer in all populations.

Immunometabolic and potential tumor-promoting changes in 3D cervical cell models infected with bacterial vaginosis-associated bacteria

AbstractSpecific bacteria of the human microbiome influence carcinogenesis at diverse anatomical sites. Bacterial vaginosis (BV) is the most common vaginal disorder in premenopausal women that is associated with gynecologic sequelae, including cervical cancer. BV-associated microorganisms, such as Fusobacterium, Lancefieldella, Peptoniphilus, and Porphyromonas have been associated with gynecologic and other cancers, though the pro-oncogenic mechanisms employed by these bacteria are poorly understood. Here, we integrated a multi-omics approach with our three-dimensional (3-D) cervical epithelial cell culture model to investigate how understudied BV-associated bacteria linked to gynecologic neoplasia influence hallmarks of cancer in vitro. Lancefieldella parvulum and Peptoniphilus lacrimalis elicited robust proinflammatory responses in 3-D cervical cells. Fusobacterium nucleatum and Fusobacterium gonidiaformans modulated metabolic hallmarks of cancer corresponding to accumulation of 2-hydroxyglutarate, pro-inflammatory lipids, and signs of oxidative stress and genotoxic hydrogen sulfide. This study provides mechanistic insights into how gynecologic cancer-associated bacteria might facilitate a tumor-promoting microenvironment in the human cervix.

Cervicovaginal DNA Virome Alterations Are Associated with Genital Inflammation and Microbiota Composition

HPV infection is an established risk factor for cervical cancer. However, more broadly, the role of the cervicovaginal virome in cervical cancer progression is not well understood.

Microbiome impacts quality of life in patients with endometrial cancer and benign gynecological conditions

Patients with endometrial cancer (EC), a prevalent gynecologic cancer in the United States, and benign gynecological conditions such as fibroids and endometriosis, experience poor quality of life (QOL). Organisms in vaginal and rectal microbiomes have been previously linked to both adverse symptoms and gynecologic disease. Using gastrointestinal, mental, physical, and sexual health symptoms as a proxy for QOL, we explored QOL relationships with vaginal and rectal microbes between patients with EC and benign gynecological conditions. Patients undergoing hysterectomy for benign or oncological indications at a single center completed QOL surveys preoperatively. The operating surgeon collected vaginal and rectal swabs prior to surgery. Survey and microbiome data were analyzed separately and then correlated utilizing MicrobiomeAnalyst, analysis of compositions of microbiomes with bias correction (ANCOM-BC), and GraphPad Prism 10.2.3. Sexual interest and Vaginal Assessment Scale (VAS) scores were higher in the benign group. Vaginal species richness was higher in the EC group. Vaginal Porphyromonas negatively correlated to sexual interest in all patients, while Dialister B positively correlated to sexual interest in the benign group. Patients with EC and worse vaginal atrophy had increased vaginal L. iners, despite adjustment for menopausal status. In the rectal microbiome, Gastranaerophilales positively correlated to good mental health and Verrucomicrobiales negatively correlated to vulvar symptoms. Identifying microbiome signatures that impact QOL in patients with EC and benign gynecological conditions increases understanding of how microbes may influence patient wellbeing. We offer preliminary findings for foundational knowledge for future opportunities on improvement of QOL through microbiome modulation.

Viewing Native American Cervical Cancer Disparities through the Lens of the Vaginal Microbiome: A Pilot Study

Abstract Vaginal dysbiosis is implicated in persistent human papillomavirus (HPV) infection and cervical cancer. Yet, there is a paucity of data on the vaginal microbiome in Native American communities. Here, we aimed to elucidate the relationships between microbiome, HPV, sociodemographic, and behavioral risk factors to better understand an increased cervical cancer risk in Native American women. In this pilot study, we recruited 31 participants (16 Native American and 15 non-Native women) in Northern Arizona and examined vaginal microbiota composition, HPV status, and immune mediators. We also assessed individuals’ sociodemographic information and physical, mental, sexual, and reproductive health. Overall, microbiota profiles were dominated by common Lactobacillus species (associated with vaginal health) or a mixture of bacterial vaginosis–associated bacteria. Only 44% of Native women exhibited Lactobacillus dominance, compared with 58% of non-Native women. Women with vaginal dysbiosis also had elevated vaginal pH and were more frequently infected with high-risk HPV. Furthermore, we observed associations of multiple people in a household, lower level of education, and high parity with vaginal dysbiosis and abundance of specific bacterial species. Finally, women with dysbiotic microbiota presented with elevated vaginal levels of proinflammatory cytokines. Altogether, these findings indicate an interplay between HPV, vaginal microbiota, and host defense, which may play a role in the cervical cancer disparity among Native American women. Future longitudinal studies are needed to determine the mechanistic role of vaginal microbiota in HPV persistence in the context of social determinants of health toward the long-term goal of reducing health disparities between non-Hispanic White and Native American populations. Prevention Relevance: Cervical cancer disproportionally affects Native American women. Sociodemographic and behavioral factors might contribute to this disparity via alteration of vaginal microbiota. Here, we show the association between these factors and vaginal dysbiosis and immune activation, which can be implicated in high-risk HPV infection among Native American and other racial/ethnic populations.

Cervicovaginal Metabolome and Tumor Characteristics for Endometrial Cancer Detection and Risk Stratification

Abstract Purpose: Endometrial cancer is highly prevalent and lacking noninvasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve the understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for noninvasive diagnostic and prognostic tests. Experimental Design: Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n = 66) and non-malignant conditions (n = 108), and global untargeted metabolomics was performed. Using the metabolite data (n = 920), we completed a multivariate biomarker discovery analysis. Results: We analyzed grade 1/2 endometrioid carcinoma (n = 53) and other endometrial cancer subtypes (n = 13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (P < 0.0001), tryptophan (P < 0.0001), and glutamate (P < 0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q < 0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Conclusions: Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement in diagnosis. The metabolic dysregulation described in this article linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighboring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of noninvasive diagnostics can improve both the acceptability and accessibility of diagnosis.