Microenvironment In Cervical Cancer Research Articles

Analysis of cancer-associated fibroblasts in cervical cancer by single-cell RNA sequencing.

Since scRNA-seq is an effective tool to study tumor heterogeneity, this paper intends to reveal the differences of cervical cancer in patients at the individual cell level by scRNA-seq, and focus on the biological functions of cancer-associated fibroblasts (CAFs) in cervical cancer, facilitating the provision of a new interpretation of the heterogeneity of the microenvironment of cervical cancer, and an in-depth exploration of the pathogenesis of cervical cancer as well as pursuit of effective means of treatment intake. 3 cervical cancer specimens were collected by clinical surgery for single-cell RNA sequencing. Cell suspensions of fresh cervical cancer tissues were prepared, and cDNA libraries were created and sequenced on the machine. Furthermore, the sequencing data were analyzed using bioinformatics, including descending clustering of cells, identification of cell populations, mimetic time series analysis, inferCNV, cell communication analysis, and identification of transcription factors. A total of 9 cell types were identified, encompassing T cells, epithelial cells, smooth muscle cells, CAFs, endothelial cells, macrophages, B cells, lymphocytes, and plasma cells. CAFs were further divided into three cell subtypes, named type1 cells, type2 cells, and type3 cells. With key transcription factors for the three cells, TCF21, ZC3H11A, and MYEF2 obtained, this research revealed the communication relationship between CAFs and several other cells, and found an important role of CAFs in the MK signaling pathway. scRNA-seq technology contributed to exploring the tumor heterogeneity of cervical cancer more deeply, and also further gaining insight into the biological functions of CAFs in cervical cancer.

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy

Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation

Magnolin (MGL), a compound derived from the magnolia plant, has inhibitory effects on tumor cell invasion and growth. His study aims to explore the antitumor effect and underlying molecular mechanism of MGL against human cervical cancer. We found that MGL inhibited the proliferation, migration, and invasiveness of cervical cancer cells in vitro and in vivo. The underlying mechanism was shown to involve MGL-induced inhibition of JNK/Sp1-mediated MMP15 transcription and translation. Overexpression of JNK/Sp1 resulted in significant restoration of MMP15 expression and the migration and invasion capabilities of MGL-treated cervical cancer cells. MGL modulated the cervical cancer microenvironment by inhibiting cell metastasis via targeting IL-10/IL-10 receptor B (IL-10RB) expression, thereby attenuating JNK/Sp1-mediated MMP15 expression. Analysis of the gut microbiota of mice fed MGL revealed a significant augmentation in Lachnospiraceae bacteria, known for their production of sodium butyrate. In vivo experiments also demonstrated synergistic inhibition of cervical cancer cell metastasis by MGL and sodium butyrate co-administration. Our study provides pioneering evidence of a novel mechanism by which MGL inhibits tumor growth and metastasis through the IL-10/IL-10RB targeting of the JNK/Sp1/MMP15 axis in human cervical cancer cells.

IL-10+CD19+ regulatory B cells induce CD4+Foxp3+regulatory T cells in serum of cervical cancer patients

Increase of regulatory T cells (Tregs) in the tumour microenvironment predicts worse survival of patients with various types of cancer. Recently, B cells play a significant role in the maintenance of Treg cells. However, the relevance of regulatory B cells (Bregs) to tumour immunity in humans remains elusive. Flow cytometry analysis was used to detect the Bregs and Tregs. Double staining results illustrated that the proportion of Bregs and Tregs were prominently higher in cervical cancer than normal tissues. Increase of Bregs and Tregs in cervical cancer microenvironment was associated with poor survival. Furthermore, Bregs cocultured with cervical cancer cell lines increased and induced Tregs. To sum up, the increased expression of Bregs contributes to the differentiation of CD4+ T cells into Tregs in the cervical cancer.

The role of BATF2 deficiency in immune microenvironment rearrangement in cervical cancer – New biomarker benefiting from combination of radiotherapy and immunotherapy

Despite the significant progress in immunotherapy for certain cancers, including cervical cancer, most patients remain unresponsive or derive limited benefits from combined radiotherapy and chemotherapy. The factors underlying treatment resistance are unknown and there are few reliable predictive biomarkers. BATF2 is a member of the basic leucine zipper transcription factor family and is involved in immune response and immune cell development. However, the role of BATF2 in the immune microenvironment of patients with cervical cancer after radiotherapy remains unclear. In this study, immunohistochemistry and multicolour immunofluorescence analyses of patient tumor samples were used to assess BATF2 expression. We found that cervical cancer patients with high BATF2 expression had higher infiltration levels of CD4+ T cells, CD8+ T cells, and macrophages within the tumor than those with low expression levels. Furthermore, BATF2 expression was positively correlated with the prognosis of patients after concurrent chemoradiotherapy. A wild-type mouse model with BATF2-knockdown U14 cell-derived subcutaneous tumors and a Batf2−/− mouse model with wild-type U14 cell-derived subcutaneous tumors were used to assess CD8+ T cell infiltration and function. As expected, the knockdown of BATF2 in the U14 cell line substantially promoted tumor growth, which was mediated by a reduction in CD8+ T cell infiltration and antitumor function in vivo. Additionally, the Batf2−/− mouse model demonstrated that host BATF2 is also involved in controlling tumor growth. Furthermore, the combination of radiotherapy and anti-PD-1 therapy showed synergistic antitumour effects. These findings collectively suggest that BATF2 may serve as a potent positive regulator of the tumor immune microenvironment of cervical cancer after radiotherapy, and has the potential to be a prognostic biomarker to guide the application of a combination of radiotherapy and immunotherapy.

Interactions of Indoleamine 2,3-dioxygenase-expressing LAMP3+ dendritic cells with CD4+ regulatory T cells and CD8+ exhausted T cells: synergistically remodeling of the immunosuppressive microenvironment in cervical cancer and therapeutic implications.

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. 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. 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. 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.

Single-Cell Analysis Reveals the Alteration of Immune Checkpoint Molecules Induced by Radiochemotherapy in Cervical Cancer Microenvironment

Radiochemotherapy (RCT) could alter the function, activation state, and distribution of immune cells in tumor microenvironment (TME). This study aimed to decipher the alteration of immune checkpoint molecules induced by RCT in the TME of cervical cancer by single-cell RNA sequencing (scRNA-seq). We analyzed the alterations of immune checkpoint molecules in the TME using scRNA-seq data of 32,116 cells from 3 pairs of tumor biopsies of cervical cancer patients pre- and post-RCT. Uniform Manifold Approximation and Projection was applied to demonstrate the heterogeneity of cell subclusters and differences in the distribution of immune checkpoint molecules. The Wilcoxon rank sum test was used to compare the expression level of the immune checkpoint molecules pre- and post-RCT. VSIR was mainly expressed on cancer-associated fibroblasts and myeloid cells, of which the level can be reduced by RCT (both P < 0.05). RCT also inhibited the expression of co-inhibitory molecules, such as HAVCR2, TIGIT, CD244, and CD160 on CD4+ T, CD8+ T, and NK cells (all P < 0.05). The expression level of co-inhibitory molecules, LAG3, and co-stimulatory molecules, TNFRSF9 on CD8+ and CD4+ T cells were reduced post-RCT (all P < 0.05). Nonetheless, the expression level of co-stimulatory molecules CD28 was significantly increased on CD4+ and CD8+ T cells post-RCT (all P < 0.05). Intriguingly, the expression level of TNFRSF18 was increased on CD8+ T cells post-RCT while it was reduced on NK cells post-RCT (both P < 0.05). This study unveils that RCT could induce complex alteration of the expression of immune checkpoint molecules on immune cells as well as stromal cells, which may help further understand the mechanism of anti-tumor effect of RCT and optimize treatment strategies.

Methionine enkephalin inhibited cervical cancer migration as well as invasion and activated CD11b+ NCR1+ NKs of tumor microenvironment

This study was to study the role of methionine enkephalin (menk) in cell invasion and migration as well as NK cells activation of tumor microenvironment in cervical cancer. The results showed that menk inhibited cervical cancer migration and invasion. In addition, we found menk affected epithelial to mesenchymal transition (EMT) related indicators, with increasing E-cadherin level, decreasing N-cadherin and vimentin level. Through in vivo mouse model, we found that menk IFNγ and NKP46 expression was upregulated in tumor tissues by menk compared with controls, while LAG3 expression was inhibited by menk, besides, there was an upregulation of CD11b+ NCR1+ NKs of tumor microenvironment in cervical cancer. Therefore, we concluded that menk inhibited cancer migration and invasion via affecting EMT related indicators and activated CD11b+ NCR1+ NKs of tumor microenvironment in cervical cancer, laying a theoretical foundation for the further clinical treatment of menk.

Sequencing-based transcriptome analysis reveals diversification of immune response- and angiogenesis-related expression patterns of early-stage cervical carcinoma as compared with high-grade CIN.

Molecular diversity of virus-associated cervical cancer remains a relatively underexplored issue, and interrelations of immunologic and angiogenic features during the establishment of a particular landscape of the cervical cancer microenvironment are not well-characterized, especially for its earliest clinical stages, although this may provide insight into the mechanisms behind the differences in tumor aggressiveness, treatment responsiveness and prognosis. In this research, we were aimed at identifying transcriptomic landscapes of early-stage cervical carcinoma that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment in comparison with immediate precursor (intraepithelial) lesions. We performed the Illumina platform-based RNA sequencing using a panel of fresh tissue samples that included human papillomavirus-positive cervical intraepithelial neoplastic lesions (CIN), invasive squamous carcinoma of the cervix of FIGO IA1-IIB stages, and morphologically normal epithelium. The derived transcriptomic profiles were bioinformatically analyzed and compared by patterns of signaling pathway activation, distribution of tumor-infiltrating cell populations, and genomic regions involved. According to hierarchical cluster analysis of the whole-transcriptome profiles, tissue samples were distributed between three groups, or gene expression patterns (the one comprising most pre-cancer cases and the other two encompassing mostly early-stage invasive cancer cases). Differentially expressed genes were retrieved in each intergroup pairwise comparison followed by Gene Ontology analysis. Gene set enrichment analysis of the two groups of tumor samples in comparison with the CIN group identified substantial differences in immunological and angiogenic properties between tumorous groups suggesting the development of different molecular phenotypes. Cell composition analysis confirmed the diverse changes in the abundancies of immune and non-immune populations and, accordingly, different impacts of the immune and stromal compartments on the tumor microenvironment in these two groups of tumors compared to CIN. Positional gene expression analysis demonstrated that the identified transcriptomic differences were linked to different chromosomal regions and co-localized with particular gene families implicated in immune regulation, inflammation, cell differentiation, and tumor invasion. Overall, detection of different transcriptomic patterns of invasive cervical carcinoma at its earliest stages supports the diverse impacts of immune response- and angiogenesis-related mechanisms on the onset of tumor invasion and progression. This may provide new options for broadening the applicability and increasing the efficiency of target anti-angiogenic and immune-based therapy of virus-associated cervical carcinoma.

TMPRSS11D/ALR-mediated ER stress regulates the function of myeloid-derived suppressor cells in the cervical cancer microenvironment

Myeloid-derived suppressor cells (MDSCs) contribute to tumor immune evasion, and have been identified as immunosuppressive cells in cervical cancer. The effect of TMPRSS11D (transmembrane serine protease 11D) in some cancers has been reported, but its role in immune escape of cervical cancer is still unclear. This study aims to elucidate the regulatory mechanism of TMPRSS11D on the immunosuppressive function of MDSCs in cervical cancer. Our data showed that the proportion of polymorphonucleoid MDSCs (PMN-MDSCs), the contents of immunosuppressive factors (including INOS, IDO, and ARG-1) secreted by MDSCs, and TMPRSS11D mRNA level in peripheral blood mononuclear cells (PBMCs) of malignant cervical cancer patients was significantly higher than that of benign tumor patients. Next, CD3+ T cells from PBMCs of cervical cancer patients were stimulated with anti-CD3 and anti-CD28, and then co-cultured with PMN-MDSCs from the same donors at a ratio of 1:2 for 3 days. PMN-MDSCs from malignant tumors produced more ROS, while TMPRSS11D knockdown blocked ROS production. PMN-MDSCs inhibited T cell proliferation and IFN-γ production, while silencing TMPRSS11D in PMN-MDSCs hindered the immunosuppressive effect of PMN-MDSCs. Mechanistically, TMPRSS11D bound to ALR (Augmenter of liver regeneration) and negatively regulated ALR expression, inducing ER stress in PMN-MDSCs, thereby enhancing the immunosuppressive effect of PMN-MDSCs on T cells. Additionally, mouse xenograft tumor assay was conducted to assess the role of TMPRSS11D in tumor growth and MDSC accumulation in vivo. Silencing TMPRSS11D impeded the growth of cervical cancer xenografts and reduced the accumulation of MDSCs in tumor tissues. In conclusion, TMPRSS11D induced ER stress in MDSCs through negative regulation of ALR, thus enhancing the immunosuppressive effect of MDSCs on T cells, so as to promote the growth of cervical cancer tumors.

Alternative splicing variants involved in pyroptosis and cuproptosis contribute to phenotypic remodeling of the tumor microenvironment in cervical cancer.

Cervical cancer (CC) remains a prevalent gynecological malignancy, posing a significant health burden among women worldwide. With the remarkable discoveries of cellular pyroptosis and cuproptosis, there has been a growing focus on exploring the intricate relationship between these two forms of cell death and their impact on tumor progression. In recent years, alternative splicing has emerged as a significant field in cancer research. Thus, the integration of alternative splicing, pyroptosis, and cuproptosis holds immense value in studying their collective impact on the occurrence and progression of cervical cancer. In this study, alternative splicing data of pyroptosis- and cuproptosis-associated genes were integrated with public databases, including TCGA, to establish a prognostic model for cervical cancer based on COX regression modeling. Subsequently, the tumor microenvironment (TME) phenotypes in the high-risk and low-risk patient groups were characterized through a comprehensive bioinformatics analysis. The findings of this study revealed that the low-risk group exhibited a predominant immune-active TME phenotype, while the high-risk group displayed a tumor-favoring metabolic phenotype. These results indicate that the alternative splicing of pyroptosis- and cuproptosis-associated genes plays a pivotal role in remodeling the phenotypic landscape of the cervical cancer TME by modulating immune responses and metabolic pathways. This study provides valuable insights into the interplay between alternative splicing variants involved in pyroptosis and cuproptosis and the TME, contributing to a deeper understanding of cervical cancer pathogenesis and potential therapeutic avenues.

Integrated immunological analysis of single-cell and bulky tissue transcriptomes reveals the role of interactions between M0 macrophages and naïve CD4+ T cells in the immunosuppressive microenvironment of cervical cancer

In recent decades, the incidence and mortality of cervical cancer have declined in developed countries due to the implementation of screening and vaccination programs. However, cervical cancer remains one of the major culprits of cancer-related deaths in young women. Current studies have found that immune cell-related intercellular communication in the tumor microenvironment has a large impact on the construction of the immunosuppressive microenvironment. In this study, we performed a comprehensive immune analysis on bulk RNA-seq and scRNA-seq data obtained from cervical cancer and revealed that two highly plastic cell populations, M0 macrophages and naïve CD4+ T cells, were significantly correlated with prognosis and clinical phenotypes. Notably, signaling between M0 macrophages and naïve CD4+ T cells as well as intracellular transcription factor activity were significantly altered in the tumor state. Furthermore, we identified overlapping genes between the transcription factor target genes of M0 macrophages or naïve CD4+ T cells and the differentially expressed genes in each type of cell, and these overlapping genes were subsequently subjected to an analysis using the LASSO regression model. Finally, we generated a score index that was significantly associated with the clinical prognosis of cervical cancer. In conclusion, interventions to improve the communication between M0 macrophages and naïve CD4+ T cells may help to improve the immunosuppressive microenvironment of cervical cancer and prevent immune evasion. The relevant molecular mechanisms need to be further validated by experimental and cohort studies.

TMEM33 as a Prognostic Biomarker of Cervical Cancer and Its Correlation with Immune Infiltration.

In women all over the world, cervical cancer (CC) ranks as the fourth most common form of cancer to be diagnosed. It was previously reported that transmembrane protein 33(TMEM33) could report a poor prognosis in several cancers. The current study is aimed at investigating the potential prognostic value of TMEM33 and its relevance to the tumor microenvironment in CC in a comprehensive manner. In this study, CC specimens presented noticeably higher TMEM33 expression level in comparison to nontumor specimens. In pan-cancer assays, it was found that TMEM33 was present at a high level in many different kinds of tumors. We found that patients with CC patients who had a high TMEM33 expression presented worse overall survival (OS) and disease-free survival (DFS) relative to patients who had a low TMEM33 expression. According to the results of a multivariate analysis, a high level of TMEM33 expression can significantly and independently predict the prognosis of CC. The levels of TMEM33 were found to have a negative correlation with resting dendritic cells, resting mast cells, plasma cells, T cells CD8, T cells regulatory, and regulatory T cells. Finally, we confirmed that TMEM33 was overexpressed in CC cells, and its knockdown distinctly suppressed the proliferation and invasion of CC cells. Overall, we provided evidences that TMEM33 could be used as a potential biomarker to assess the prognosis and the level of immune infiltration in CC.

Association of Glycosylation-Related Genes with Different Patterns of Immune Profiles and Prognosis in Cervical Cancer.

(1) Background: Although the application of modern diagnostic tests and vaccination against human papillomavirus has markedly reduced the incidence and mortality of early cervical cancer, advanced cervical cancer still has a high death rate worldwide. Glycosylation is closely associated with tumor invasion, metabolism, and the immune response. This study explored the relationship among glycosylation-related genes, the immune microenvironment, and the prognosis of cervical cancer. (2) Methods and results: Clinical information and glycosylation-related genes of cervical cancer patients were downloaded from the TCGA database and the Molecular Signatures Database. Patients in the training cohort were split into two subgroups using consensus clustering. A better prognosis was observed to be associated with a high immune score, level, and status using ESTIMATE, CIBERSORT, and ssGSEA analyses. The differentially expressed genes were revealed to be enriched in proteoglycans in cancer and the cytokine-cytokine receptor interaction, as well as in the PI3K/AKT and the Hippo signaling pathways according to functional analyses, including GO, KEGG, and PPI. The prognostic risk model generated using the univariate Cox regression analysis, LASSO algorithm and multivariate Cox regression analyses, and prognostic nomogram successfully predicted the survival and prognosis of cervical cancer patients. (3) Conclusions: Glycosylation-related genes are correlated with the immune microenvironment of cervical cancer and show promising clinical prediction value.

Cervical cancer immune infiltration microenvironment identification, construction of immune scores, assisting patient prognosis and immunotherapy.

The immune microenvironment is of great significance in cervical cancer. However, there is still a lack of systematic research on the immune infiltration environment of cervical cancer. We obtained cervical cancer transcriptome data and clinical information from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, evaluated the immune microenvironment of cervical cancer, determined immune subsets, constructed an immune cell infiltration scoring system, screened key immune-related genes, and performed single-cell data analysis and cell function analysis of key genes. We combined the TCGA and GEO data sets and obtained three different immune cell populations. We obtained two gene clusters, extracted 119 differential genes, and established an immune cell infiltration (ICI) scoring system. Finally, three key genes, IL1B, CST7, and ITGA5, were identified, and single-cell sequencing data were mined to distribute these key genes in different cell types. By up-regulating CST7 and down-regulating IL1B and ITGA5, cervical cancer cells' proliferation ability and invasion ability were successfully reduced. We conducted a comprehensive assessment of the state of the tumor immune microenvironment in cervical cancer, constructed the ICI scoring system, and identified the ICI scoring system as a potential indicator of susceptibility to immunotherapy for cervical cancer, identifying key genes suggesting that IL1B, CST7, and ITGA5 play an essential role in cervical cancer.

Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes.

Increasing evidence suggests that diverse activation patterns of metabolic signalling pathways may lead to molecular diversity of cervical cancer (CC). But rare research focuses on the alternation of fatty acid metabolism (FAM) in CC. Therefore, we constructed and compared models based on the expression of FAM-related genes from the Cancer Genome Atlas by different machine learning algorithms. The most reliable model was built with 14 significant genes by LASSO-Cox regression, and the CC cohort was divided into low-/high-risk groups by the median of risk score. Then, a feasible nomogram was established and validated by C-index, calibration curve, net benefit, and decision curve analysis. Furthermore, the hub genes among differential expression genes were identified and the post-transcriptional and translational regulation networks were characterized. Moreover, the somatic mutation and copy number variation landscapes were depicted. Importantly, the specific mutation drivers and signatures of the FAM phenotypes were excavated. As a result, the high-risk samples were featured by activated de novo fatty acid synthesis, epithelial to mesenchymal transition, angiogenesis, and chronic inflammation response, which might be caused by mutations of oncogenic driver genes in RTK/RAS, PI3K, and NOTCH signalling pathways. Besides the hyperactivity of cytidine deaminase and deficiency of mismatch repair, the mutations of POLE might be partially responsible for the mutations in the high-risk group. Next, the antigenome including the neoantigen and cancer germline antigens was estimated. The decreasing expression of a series of cancer germline antigens was identified to be related to reduction of CD8 T cell infiltration in the high-risk group. Then, the comprehensive evaluation of connotations between the tumour microenvironment and FAM phenotypes demonstrated that the increasing risk score was related to the suppressive immune microenvironment. Finally, the prediction of therapy targets revealed that the patients with high risk might be sensitive to the RAF inhibitor AZ628. Our findings provide a novel insight for personalized treatment in CC.

A prognostic hypoxia gene signature is associated with a dampened tumour immune microenvironment in cervical cancer

Background: Hypoxia, or low oxygen, is a condition that is characteristic of solid tumours, including cervical cancer. Hypoxia is associated with worse survival in this disease and supports tumorigenic characteristics of stemness, survival, metastasis and angiogenesis, as well as immune resistance. Aims: In this work, we aimed to determine the prognostic significance of a previously derived in vitro eight-gene hypoxia signature in cervical cancer, and to investigate the interplay between the hypoxic and immune features of the cervical tumour microenvironment (TME). Subjects and Methods: The 240 patients with cervical squamous cell carcinoma obtained from the Cancer Genome Atlas Pan-Cancer study were first given a hypoxia score and an immune score (IS) and subsequently subjected to survival analysis. CIBERSORTx was also applied to determine the fractions of immune cells residing in the hypoxia high versus hypoxia low patient groups. Results: We show that the eight-gene hypoxia signature is predictive of worse prognosis in patients with cervical cancer and is associated with a less immunogenic TME. Furthermore, by combining the hypoxia score with an IS to stratify patients based on both their hypoxic and immune status, we achieve an enhancement in survival prediction, with the hypoxia high/immune low subgroup of patients showing the worse probability of overall and disease-specific survival. Conclusions: It is clear from this work that the interplay between the hypoxic and immune microenvironment can contribute to cervical cancer patients' survival. Furthermore, patients with tumours that are both highly hypoxic and immune deprived should be considered for hypoxia-targeted therapy when planning treatment modalities to improve survival.

Immune infiltration could predict the efficacy of short-term radiotherapy in patients with cervical cancer.

Radiotherapyis the main treatment forcervical cancer. It is usually applied alone or in combination with surgery and/or chemotherapy. To explore the association between immune microenvironment of cervical cancer and radiotherapy response, we collected 20 paired cervical cancer tumor samples before and after radiotherapy and partial clinical information. With paired-end RNA-seq, we quantified the immune infiltration and tumor purity of these samples, and obtained 6350 differentially expressed genes before and after radiotherapy. With the help of R language, the function enrichment analysis and 22 immune cells infiltration analysis were carried out. Moreover, we built a random forest model based on the immune microenvironment to predict the short-term efficacy of radiotherapy. We found that the effect of radiotherapy on the immune microenvironment of stage III and IV cervical cancer patients was weaker than that of stage I and II cervical cancer patients. Radiotherapy can significantly reduce the tumor purity and increase immune infiltration. The proportions of the immune infiltrating cells are predictive of the radiotherapy efficacy. In addition, the local mucositis caused by radiotherapy can improve the curative effect of radiotherapy.

HPV-Related Cervical Cancer and Extracellular Vesicles

Cervical cancer is the fourth most common type of cancer in females worldwide. Infection with a human papillomavirus is crucial to the etiopathogenesis of cervical cancer. The natural trajectory of HPV infection comprises HPV acquisition, HPV persistence versus clearance, and progression to precancer and invasive cancer. The majority of HPV infections are cleared and controlled by the immune system within 2 years, but some infections may become quiescent or undetectable. The persistence of high-risk HPV infection for a longer period of time enhances the risk of malignant transformation of infected cells; however, the mechanisms responsible for the persistence of infection are not yet well-understood. It is estimated that 10-15% of infections do persist, and the local microenvironment is now recognized as an important cofactor promoting infection maintenance. Extracellular vesicles (EVs) are small membrane vesicles derived from both normal cells and cancer cells. EVs contain various proteins, such as cytoskeletal proteins, adhesion molecules, heat shock proteins, major histocompatibility complex, and membrane fusion proteins. EVs derived from HPV-infected cells also contain viral proteins and nucleic acids. These biologically active molecules are transferred via EVs to target cells, constituting a kind of cell-to-cell communication. The viral components incorporated into EVs are transmitted independently of the production of infectious virions. This mode of transfer makes EVs a perfect vector for viruses and their components. EVs participate in both physiological and pathological conditions; they have also been identified as one of the mediators involved in cancer metastasis. This review discusses the potential role of EVs in remodeling the cervical cancer microenvironment which may be crucial to tumor development and the acquisition of metastatic potential. EVs are promising as potential biomarkers in cervical cancer.

A novel prognostic biomarker CD3G that correlates with the tumor microenvironment in cervical cancer

Cervical cancer (CESC) is the fourth most common and death-causing gynecological cancer, mostly induced by infection of human papillomavirus (HPV). Multiple components of the tumor microenvironment (TME), such as tumor infiltrating immune cells, could be targets of immunotherapy for HPV-related CESC. However, little is known about the TME of CESC until now. Here, we aimed to uncover the pathogenesis as well as to identify novel biomarkers to predict prognosis and immunotherapy efficacy for CESC. Combining the transcriptomic data and clinical characteristics, we identified differentially expressed genes in CESC samples from TCGA database by comparing the two groups with different ImmuneScore and StromalScore. Next, we detected ten key genes based on the PPI network and survival analyses with the univariate Cox regression model. Thereafter, we focused on CD3G, the only gene exhibiting increased RNA and protein expression in tumors by multiple analyses. Higher CD3G expression was associated with better survival; and it was also significantly associated with immune-related pathways through GSEA analysis. Furthermore, we found that CD3G expression was correlated with 16 types of TICs. Single cell RNA-sequencing data of CD3G in lymphocytes subgroup indicated its possible role in HPV defense. Hence, CD3G might be a novel biomarker in prognosis and immunotherapy for CESC patients.