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Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes.

ABSTRACT: Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

SUBMITTER: Li C

PROVIDER: S-EPMC9263187 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

Project description:BackgroundLymph node metastasis in the cervical region posterior to level V (PLV) can occurs in patients with nasopharyngeal carcinoma (NPC), but the significance of lymph node metastasis in this region and the delineation of the radiotherapy target area have not been reported. We aimed to explore the distribution pattern and prognosis of metastatic lymph nodes in the PLV region in patients with NPC.MethodsWe retrospectively studied 605 cases of NPC diagnosed by pathological detection from December 2011 to November 2017. The nodal distribution at each level was assessed in accordance with the Radiation Therapy Oncology Group (RTOG) guidelines proposed in 2013. The central points of the metastatic lymph nodes of the PLV region in the patients were recreated proportionally on the CT images of a standard patient with N0 NPC in reference to the normal anatomy of the PLV area. The correlation between the PLV region and the other levels, the nodal location, and the characteristics and prognosis of the PLV region were analyzed.ResultsLymph node metastasis occurred in 557 (92.06%) of 605 patients. There were 30 patients (4.95%) with lymph node metastasis in the PLV region. A total of 49 metastatic lymph nodes from the PLV region were counted, and the mean vertical distance of the central point of each lymph node from the anterior surface of the trapezius muscle was 14 mm. Linear regression correlation analysis suggested that lymph node metastasis in the PLV region was associated with ipsilateral level IVa (P = 0.018), level Va, level Vb, and level Vc lymph node metastasis (all P < 0.001). The 5-year OS, PFS, LRFS, and DMFS of 29 patients with lymph node metastasis in the PLV region were 41.6, 27.7, 89.1, and 47.3%, respectively. Multivariate analysis showed that lymph node metastasis in the PLV region was an independent prognostic factor for DMFS (P < 0.05).ConclusionNPC patients with lymph node metastasis in the PLV region had a poor prognosis and a high risk of distant metastasis. We recommend that the margin of the PLV region may be a new cervical lymph node segment for NPC.

Project description:BackgroundThe Node Reporting and Data System (Node-RADS) is a recently proposed classification system for the categorization of lymph nodes in radiological images. This study was conducted to retrospectively evaluate the diagnostic accuracy of the Node-RADS score for metastatic cervical lymph nodes on magnetic resonance imaging (MRI) of patients with nasopharyngeal carcinoma (NPC).MethodsWe retrospectively analyzed cervical lymph nodes of NPC cases. Two radiologists independently evaluated each lymph node on the MRI scans using Node-RADS. Interobserver agreement between 2 radiologists for Node-RADS score assessment was evaluated by linear weighted kappa statistics. The correlation between metastasis and the Node-RADS score of each lymph node was analyzed using multivariate regression analysis. To investigate the diagnostic performance of the Node-RADS score, we further conducted receiver operating characteristic curve analysis. Correspondently, the sensitivity, specificity, positive predictive value, and negative predictive value of each different cutoff (>1, >2, >3, and >4) were computed.ResultsIn all, 119 patients with NPC were assessed, including 203 cervical lymph nodes consisting of 140 (69%) of 203 metastatic and 63 (31%) of 203 benign. The kappa agreement between the 2 readers for the Node-RADS score was 0.863 (95% CI = 0.830-0.897, P < .001). Node-RADS score on MRI scan was shown to be an independent predictive factor of lymph node metastasis after multivariate regression analysis (odds ratio [OR] = 6.745, 95% CI = 3.964-11.474, P < .001). Node-RADS achieved an area under the curve (AUC) of 0.950 (95% CI = 0.921-0.979) in diagnosing metastatic lymph nodes. When Node-RADS >2 was identified as the best cutoff based on balanced values, the sensitivity and positive predictive value were 0.92 and 0.94, respectively.ConclusionsOur study suggests that the Node-RADS score has high accuracy in predicting NPC cervical lymph node metastasis. Nevertheless, this conclusion requires confirmation in a larger cohort of patients with NPC.

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Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes.

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