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Background: Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets., Methods: We conducted single-cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high-grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3-dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two-tailed Student's t-test, Mann-Whitney test, or Kruskal-Wallis test to compare continuous data between two groups and one-way ANOVA with Tukey's post hoc test to compare data between multiple groups., Results: Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal-associated membrane protein 3-positive (LAMP3 + ) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor-reactive exhausted CD8 + T cells and CD4 + regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co-localization of neoantigen-reactive T cells (CD3 + , CD4 + /CD8 + , and PD-1 + ) and LAMP3 + DCs (CD80 + and PD-L1 + ). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone., Conclusions: Our study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC., (© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of SUN YAT-SEN UNIVERSITY CANCER CENTER.)

Cervical adenocarcinomas (ADCs), including human papillomavirus (HPV)-associated (HPVA) and non-HPVA (NHPVA), though exhibiting a more malignant phenotype and poorer prognosis, are treated identically to squamous cell carcinoma (SCC). This clinical dilemma requires a deeper investigation into their differences. Herein a transcriptomic atlas of SCC, HPVA, and NHPVA-ADC using single-cell RNA (scRNA) and T-cell receptor sequencing (TCR-seq) is presented. Regarding structural cells, the malignancy origin of epithelial cells, angiogenic tip cells and two subtypes of fibroblasts is revealed. The promalignant properties of the structural cells using organoids are further confirmed. Regarding immune cells, myeloid cells with multiple functions other than antigen presentation and exhausted T lymphocytes contribute to immunosuppression. From the perspective of HPV infection, not only is HPV-dependent and independent cervical cancer oncogenesis proposed but also three immune reaction patterns mediated by T cells (coordinated/inactive/imbalanced) are identified. Strikingly, diagnostic biomarkers to distinguish ADC from SCC are discovered and prognostic biomarkers with marker genes for malignant epithelial cells, tip cells, and SPP1/C1QC macrophages are generated. Importantly, the efficacy of anti-CD96 and anti-TIGIT, not inferior to anti-PD1, in animal experiments is confirmed and targeted therapies specifically for HPV-positive SCC, HPVA and NHPVA-ADC, providing essential clues for further clinical trials, are proposed., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: The mechanism underlying cervical carcinogenesis that is mediated by persistent human papillomavirus (HPV) infection remains elusive., Aims: Here, for the first time, we deciphered both the temporal transition and spatial distribution of cellular subsets during disease progression from normal cervix tissues to precursor lesions to cervical cancer., Materials & Methods: We generated scRNA-seq profiles and spatial transcriptomics data from nine patient samples, including two HPV-negative normal, two HPV-positive normal, two HPV-positive HSIL and three HPV-positive cancer samples., Results: We not only identified three 'HPV-related epithelial clusters' that are unique to normal, high-grade squamous intraepithelial lesions (HSIL) and cervical cancer tissues but also discovered node genes that potentially regulate disease progression. Moreover, we observed the gradual transition of multiple immune cells that exhibited positive immune responses, followed by dysregulation and exhaustion, and ultimately established an immune-suppressive microenvironment during the malignant program. In addition, analysis of cellular interactions further verified that a 'homeostasis-balance-malignancy' change occurred within the cervical microenvironment during disease progression., Discussion: We for the first time presented a spatiotemporal atlas that systematically described the cellular heterogeneity and spatial map along the four developmental steps of HPV-related cervical oncogenesis, including normal, HPV-positive normal, HSIL and cancer. We identified three unique HPV-related clusters, discovered critical node genes that determined the cell fate and uncovered the immune remodeling during disease escalation., Conclusion: Together, these findings provided novel possibilities for accurate diagnosis, precise treatment and prognosis evaluation of patients with precancer and cervical cancer., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Considering the unique biological behavior of cervical adenocarcinoma (AC) compared to squamous cell carcinoma, we now lack a distinct method to assess prognosis for AC patients, especially for intermediate-risk patients. Thus, we sought to establish a Silva-based model to predict recurrence specific for the intermediate-risk AC patients and guide adjuvant therapy., Methods: 345 AC patients were classified according to Silva pattern, their clinicopathological data and survival outcomes were assessed. Among them, 254 patients with only intermediate-risk factors were identified. The significant cutoff values of four factors (tumor size, lymphovascular space invasion (LVSI), depth of stromal invasion (DSI) and Silva pattern) were determined by univariate and multivariate Cox analyses. Subsequently, a series of four-, three- and two-factor Silva-based models were developed via various combinations of the above factors., Results: (1) We confirmed the prognostic value of Silva pattern using a cohort of 345 AC patients. (2) We established Silva-based models with potential recurrence prediction value in 254 intermediate-risk AC patients, including 12 four-factor models, 30 three-factor models and 16 two-factor models. (3) Notably, the four-factor model, which includes any three of four intermediate-risk factors (Silva C, ≥ 3 cm, DSI > 2/3, and > mild LVSI), exhibited the best recurrence prediction performance and surpassed the Sedlis criteria., Conclusions: Our study established a Silva-based four-factor model specific for intermediate-risk AC patients, which has superior recurrence prediction performance than Sedlis criteria and may better guide postoperative adjuvant therapy., (© 2022. The Author(s).)

Objective: To evaluate the prognostic performance of the revised 2018 FIGO staging system for cervical cancer., Methods: This retrospective multicenter study enrolled cervical cancer patients with 2009 FIGO Stage IA1-IIA2 who underwent surgeries between January 2006 and December 2017 in four tertiary hospitals. Patients were restaged according to the 2018 FIGO staging system by reviewing their medical data., Results: Of 3238 cervical cancer patients included, 1841 (56.9%) patients were restaged: 641 (34.9%) due to tumor size, 544 (29.5%) due to lymph node metastasis, 614 (33.4%) due to the inconsistency between pre- and postoperative assessments, and 42 due to the cancellation of invasion width in Stage IA. After restaging, a clear tendency of decreased recurrence-free survival (RFS) and overall survival (OS) with increasing stage was observed. Multivariate Cox analysis showed that 2018 FIGO stage, parametrial involvement, and histology were independent prognostic factors for both OS and RFS (P < 0.05). Based on these factors, we established predictive nomograms with c-indexes of 0.735 and 0.721, showing good predictive ability for cervical cancer., Conclusion: The revised 2018 FIGO staging system can better reflect the survival of cervical cancer patients. Based on it, we established a nomogram that can predict the prognosis of cervical cancer patients more precisely., (© 2021 International Federation of Gynecology and Obstetrics.)

Introduction: Cervical cancer has high mortality, high recurrence and poor prognosis. Although prognostic biomarkers such as clinicopathological features have been proposed, their accuracy and precision are far from satisfactory. Therefore, novel biomarkers are urgently needed for disease surveillance, prognosis prediction and treatment selection., Materials: Differentially expressed genes (DEGs) between cervical cancer and normal tissues from three microarray datasets extracted from the Gene Expression Omnibus platform were identified and screened. Based on these DEGs, a six-gene prognostic signature was constructed using cervical squamous cell carcinoma and endocervical adenocarcinoma data from The Cancer Genome Atlas. Next, the molecular functions and related pathways of the six genes were investigated through gene set enrichment analysis and co-expression analysis. Additionally, immunophenoscore analysis and the QuartataWeb Server were employed to explore the therapeutic value of the six-gene signature., Results: We discovered 178 overlapping DEGs in three microarray datasets and established a six-gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) prognostic signature with stable and excellent performance in predicting overall survival in different subgroups. Intriguingly, the six-gene signature was closely associated with the immune response and tumour immune microenvironment. The six-gene signature might be used for predicting response to immune checkpoint inhibitors (ICIs) and the six genes may serve as new drug targets for cervical cancer., Conclusion: Our study established a novel six-gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) signature that was closely associated with the immune response and tumour immune microenvironment. The six-gene signature was indicative of aggressive features of cervical cancer and therefore might serve as a promising biomarker for predicting not only overall survival but also ICI treatment effectiveness. Moreover, three genes (UPP1, ISG20 and GLTP) within the six-gene signature have the potential to become novel drug targets., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Endocervical adenocarcinoma (EAC) is an aggressive type of endocervical cancer. At present, molecular research on EAC mainly focuses on the genome and mRNA transcriptome, the investigation of small RNAs in EAC has not been fully described. Here, we systematically explored small RNAs in 14 EAC patients with different subtypes using small RNA sequencing. MiRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads and the total number of miRNAs and tDRs maintained a relative balance. To explore the correlations between small RNAs expression and EAC with different clinical characteristics, we performed the weighted gene co-expression network analysis (WGCNA) and screened for hub small RNAs. From the key modules, we identified 9 small RNAs that were significantly related to clinical characteristics in EAC patients. Gene ontology and pathway analyses revealed that these molecules were involved in the pathogenesis of EAC. Our work provided new insights into EAC pathogenesis and successfully identified several small RNAs as candidate biomarkers for diagnosis and prognosis of EAC.

Objective: To compare the characteristics, surgical complications, and overall survival between patients undergoing laparoscopy versus laparotomy for treatment of early-stage cervical stump carcinoma., Methods: Patients with International Federation of Gynecology and Obstetrics (FIGO, 2009) stage IA2 to IIA2 cervical stump carcinoma who underwent laparoscopy or laparotomy in the Obstetrics and Gynecology Hospital of Fudan University from January 2000 to June 2018 were retrospectively reviewed. All patients' clinical characteristics, pathological features, complications, and follow-up data were retrieved., Results: Seventy-two patients were included in the analysis; 58 underwent laparoscopy and 14 underwent laparotomy. With respect to surgical complications, laparoscopy was associated with a significantly lower complication rate, less blood loss, a shorter operative time, and a higher hospitalization fee than laparotomy. Survival was not significantly different between the laparoscopy and laparotomy groups., Conclusions: Although survival was not significantly different between the two surgical approaches, the rate of surgical complications was much lower in the laparoscopy than laparotomy group.

Objective: To compare survival outcomes of minimally invasive surgery (MIS) and laparotomy in early-stage cervical cancer (CC) patients., Methods: A multicenter retrospective cohort study was conducted with International Federation of Gynecology and Obstetrics (FIGO, 2009) stage IA1 (lymphovascular invasion)-IIA1 CC patients undergoing MIS or laparotomy at four tertiary hospitals from 2006 to 2017. Propensity score matching and weighting and multivariate Cox regression analyses were performed. Survival was compared in various matched cohorts and subgroups., Results: Three thousand two hundred and fifty-two patients (2439 MIS and 813 laparotomy) were included after matching. (1) The 2- and 5-year recurrence-free survival (RFS) (2-year, hazard ratio [HR], 1.81;95% confidence interval [CI], 1.09-3.0; 5-year, HR, 2.17; 95% CI, 1.21-3.89) or overall survival (OS) (2-year, HR, 1.87; 95% CI, 1.03-3.40; 5-year, HR, 2.57; 95% CI, 1.29-5.10) were significantly worse for MIS in patients with stage I B1, but not the cohort overall (2-year RFS, HR, 1.04; 95% CI, 0.76-1.42; 2-year OS, HR, 0.99; 95% CI, 0.70-1.41; 5-year RFS, HR, 1.12; 95% CI, 0.76-1.65; 5-year OS, HR, 1.20; 95% CI, 0.79-1.83) or other stages (2) In a subgroup analysis, MIS exhibited poorer survival in many population subsets, even in patients with less risk factors, such as patients with squamous cell carcinoma, negative for parametrial involvement, with negative surgical margins, negative for lymph node metastasis, and deep stromal invasion < 2/3. (3) In the cohort treated with (2172, 54%) or without adjuvant treatment (1814, 46%), MIS showed worse RFS than laparotomy in patients treated without adjuvant treatment, whereas no differences in RFS and OS were observed in adjuvant-treatment cohort. (4) Inadequate surgeon proficiency strongly correlated with poor RFS and OS in patients receiving MIS compared with laparotomy., Conclusions: MIS exhibited poorer survival outcomes than laparotomy group in many population subsets, even in low-risk subgroups. Therefore, laparotomy should be the recommended approach for CC patients., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)