Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment
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ABSTRACT:
SUBMITTER: Guangxu Cao
PROVIDER: S-SCDT-10_15252-EMBJ_2022110757 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BackgroundCervical cancer is one of the most common gynecological cancers worldwide. The tumor microenvironment significantly influences the therapeutic response and clinical outcome. However, the complex tumor microenvironment of cervical cancer and the molecular mechanisms underlying chemotherapy resistance are not well studied. This study aimed to comprehensively analyze cells from pretreated and chemoresistant cervical cancer tissues to generate a molecular census of cell populations.MethodsBiopsy tissues collected from patients with cervical squamous cell carcinoma, cervical adenocarcinoma, and chronic cervicitis were subjected to single-cell RNA sequencing using the 10× Genomics platform. Unsupervised clustering analysis of cells was performed to identify the main cell types, and important cell clusters were reclustered into subpopulations. Gene expression profiles and functional enrichment analysis were used to explore gene expression and functional differences between cell subpopulations in cervicitis and cervical cancer samples and between chemoresistant and chemosensitive samples.ResultsA total of 24,371 cells were clustered into nine separate cell types, including immune and non-immune cells. Differentially expressed genes between chemoresistant and chemosensitive patients enriched in the phosphoinositide 3-kinase (PI3K)/AKT pathway were involved in tumor development, progression, and apoptosis, which might lead to chemotherapy resistance.ConclusionsOur study provides a comprehensive overview of the cancer microenvironment landscape and characterizes its gene expression and functional difference in chemotherapy resistance. Consequently, our study deepens the insights into cervical cancer biology through the identification of gene markers for diagnosis, prognosis, and therapy.
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Project description:Tumor budding (TB) histology has become a critical biomarker for several solid cancers. Despite the accumulating evidence for the association of TB histology with poor prognosis, the biological characteristics of TB are little known about in the context related to the tumor immune microenvironment (TIME) in uterine cervical cancer (CC). Therefore, this study aimed to identify the transcriptomic immune profiles related to TB status and further provide robust medical evidence for clinical application. In our study, total RNA was extracted and sequenced from 21 CC tissue specimens. As such, 1494 differentially expressed genes (DEGs) between the high- and low-TB groups were identified by DESeq2. After intersecting the list of DEGs and public immune genes, we selected 106 immune-related DEGs. Then, hub genes were obtained using Least Absolute Shrinkage and Selection Operator regression. Finally, the correlation between the hub genes and immune cell types was analyzed and four candidate genes were identified (one upregulated (FCGR3B) and three downregulated (ROBO2, OPRL1, and NR4A2) genes). These gene expression levels were highly accurate in predicting TB status (area under the curve >80%). Interestingly, FCGR3B is a hub gene of several innate immune pathways; its expression significantly differed in the overall survival analysis (p = 0.0016). In conclusion, FCGR3B, ROBO2, OPRL1, and NR4A2 expression can strongly interfere with TB growth and replace TB to stratify CC patients.
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Project description:AimTo investigate the correlation between clinicopathological features and risk stratification in cervical cancer patients, and evaluate the feasibility of tumor-infiltrating immune cells as prognostic biomarkers in clinical practice.MethodsCD3+ tumor infiltrating T cells (TILs), CD45RO+ TILs, CD4+ TILs, CD8+ TILs, FOXP3+ TILs (regulatory T cells, Tregs), CD68+ tumor associated macrophages (TAMs), CD163+ TAMs, and PD-L1+ tumor cells were immunostained in formalin-fixed paraffin-embedded (PPFE) tissues from 96 cervical cancer patients. Immunostaining density and other clinicopathological features such as age, FIGO stage, histopathologic type, Ki67 index, HPV status, lymhovasular invasion status (LVI), lymph node metastasis, tumor size, stromal invasion status, surgical margin status, and parametrial invasion, were evaluated for their roles in risk stratification of cervical cancer patients.ResultsThe results showed that significant differences of lymph node metastasis (p = 0.003), surgical margin status (p = 0.020), and stromal invasion status (p = 0.004) existed between lVI(-) and LVI(+) patients. CD3+ TILs in the central tumor area (p = 0.010), CD4+ TILs in the central tumor area (p = 0.045), CD8 + TILs in the central tumor area (p = 0.033), and CD8+ TILs in the invasive margin area (p = 0.004) showed significant differences between lVI(-) and LVI(+) patients. When patients were grouped by status of lymph node metastasis, significant differences of FIGO stage (p = 0.005), LVI status (p = 0.003), CD3+ TILs in the central tumor area (p = 0.045), CD45RO+ TILs in the central tumor area (p = 0.033), and CD45RO+ TILs in the invasive margin area (p = 0.028) were also observed. After the patients were stratified into low-, intermediate-, and high risk groups, significant differences of FIGO stage (p = 0.018), status of lymph node metastasis (p = 0.000), LVI status (p = 0.000), parametrial invasion status (p=0.012), stromal invasion status (p = 0.000), tumor growth pattern (p = 0.015) and tumor size (p = 0.000) were identified among 3 groups of patients, while only CD45RO+ TILs in the invasive margin area (p = 0.018) and FOXP3+ TILs in the central tumor area (p = 0.009) were statistically different among three groups of patients. Spearman's correlation analysis demonstrated that FIGO stage, LVI status, status of lymph node metastasis, parametrial invasion, stromal invasion status, and tumor size positively correlated with risk stratification (P = 0.005, 0.020, 0.000, 0.022, 0.000, and 0.000 respectively), while CD45RO+ TILs in the invasive margin area and FOXP3+ TILs in the central tumor area showed statistically negative correlation with risk stratification (P = 0.031, 0.009 respectively).ConclusionOur study suggested that CD45RO+ TILs in the invasive margin area and FOXP3+ TILs in the central tumor area might be useful biomarkers for risk stratification in cervical cancer patients. Large cohort studies of cervical cancer patients are required to validate our hypothesis.
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