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Single-Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma.

ABSTRACT: The effective treatment of advanced cervical cancer remains challenging. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial enhanced resolution omics-sequencing (Stereo-seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non-cancer samples, except for LGALS9 and IDO1. Stronger signals of CD56⁺ NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, whereas more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of pro-tumorigenic cancer-associated myofibroblasts (myCAFs) are identified. The myCAFs may support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling of the tumor extracellular matrix. Furthermore, these myCAFs are associated with poorer survival probability in patients with CSCC, predict resistance to immunotherapy, and might be present in a small fraction (< 30%) of patients with advanced cancer. Immunohistochemistry and multiplex immunofluorescence staining are conducted to validate the spatial distribution and potential function of myCAFs. Collectively, these findings enhance the understanding of the immunological microenvironment of CSCC and shed light on the treatment of advanced CSCC.

SUBMITTER: Ou Z

PROVIDER: S-EPMC9561780 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Single-Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma.

Ou Zhihua Z Lin Shitong S Qiu Jiaying J Ding Wencheng W Ren Peidi P Chen Dongsheng D Wang Jiaxuan J Tong Yihan Y Wu Di D Chen Ao A Deng Yuan Y Cheng Mengnan M Peng Ting T Lu Haorong H Yang Huanming H Wang Jian J Jin Xin X Ma Ding D Xu Xun X Wang Yanzhou Y Li Junhua J Wu Peng P

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220819 29

The effective treatment of advanced cervical cancer remains challenging. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial enhanced resolution omics-sequencing (Stereo-seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non-cancer samples, except for LGALS9 and IDO1. Stronger signals o ...[more]

PMID: 35986392

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Project description:BackgroundCervical cancer (CC) is the 3rd most common cancer in women and the 4th leading cause of deaths in gynaecological malignancies, yet the exact progression of CC is inconclusive, mainly due to the high complexity of the changing tumour microenvironment (TME) at different stages of tumorigenesis. Importantly, a detailed comparative single-nucleus transcriptomic analysis of tumour microenvironment (TME) of CC patients at different stages is lacking.MethodsIn this study, a total of 42,928 and 29,200 nuclei isolated from the tumour tissues of stage-I and II CC patients and subjected to single-nucleus RNA sequencing (snRNA-seq) analysis. The cell heterogeneity and functions were comparatively investigated using bioinformatic tools. In addition, label-free quantitative mass spectrometry based proteomic analysis was carried out. The proteome profiles of stage-I and II CC patients were compared, and an integrative analysis with the snRNA-seq was performed.ResultsCompared with the stage-I CC (CCI) patients, the immune response relevant signalling pathways were largely suppressed in various immune cells of the stage-II CC (CCII) patients, yet the signalling associated with cell and tissue development was enriched, as well as metabolism for energy production suggested by the upregulation of genes associated with mitochondria. This was consistent with the quantitative proteomic analysis that showed the dominance of proteins promoting cell growth and intercellular matrix development in the TME of CCII group. The interferon-α and γ responses appeared the most activated pathways in many cell populations of the CCI patients. Several collagens, such as COL12A1, COL5A1, COL4A1 and COL4A2, were found significantly upregulated in the CCII group, suggesting their roles in diagnosing CC progression. A novel transcript AC244205.1 was detected as the most upregulated gene in CCII patients, and its possible mechanistic role in CC may be investigated further.ConclusionsOur study provides important resources for decoding the progression of CC and set the foundation for developing novel approaches for diagnosing CC and tackling the immunosuppressive TME.

Project description:JOURNAL/nrgr/04.03/01300535-202511000-00032/figure1/v/2024-12-20T164640Z/r/image-tiff Glial cells play crucial roles in regulating physiological and pathological functions, including sensation, the response to infection and acute injury, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system, and satellite glial cells and Schwann cells in the peripheral nervous system. Despite the greater understanding of glial cell types and functional heterogeneity achieved through single-cell and single-nucleus RNA sequencing in animal models, few studies have investigated the transcriptomic profiles of glial cells in the human spinal cord. Here, we used high-throughput single-nucleus RNA sequencing and spatial transcriptomics to map the cellular and molecular heterogeneity of astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these findings with those from mice. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were each divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into five, four, and five distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cell types between humans and mice. Additionally, we detected sex differences in gene expression in human spinal cord glial cells. Specifically, in all astrocyte subtypes, the levels of NEAT1 and CHI3L1 were higher in males than in females, whereas the levels of CST3 were lower in males than in females. In all microglial subtypes, all differentially expressed genes were located on the sex chromosomes. In addition to sex-specific gene differences, the levels of MT-ND4 , MT2A , MT-ATP6 , MT-CO3 , MT-ND2 , MT-ND3 , and MT-CO2 in all spinal cord oligodendrocyte subtypes were higher in females than in males. Collectively, the present dataset extensively characterizes glial cell heterogeneity and offers a valuable resource for exploring the cellular basis of spinal cord-related illnesses, including chronic pain, amyotrophic lateral sclerosis, and multiple sclerosis.

Project description:BackgroundCervical squamous cell carcinoma (CSCC), caused by the infection of high-risk human papillomavirus, is one of the most common malignancies in women worldwide.MethodsRNA expression data, including those from the Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases, were used to identify the expression of RNAs in normal and tumor tissue. Correlation analysis was performed to identify the immune-related long noncoding RNAs (IRLs) and hypoxia-related genes (IRHs) that can influence the activity of the immune system. Prognosis models of immune-related RNAs (IRRs) were used to construct a coexpression network of the immune system. We identified the role of IRRs in immunotherapy by correlation analysis with immune checkpoint genes (ICGs). We then validated the expression data by integrating two single-cell sequencing data sets of CSCC to identify the key immune features.ResultsIn total, six immune-related gene (IRG), four IRL, and five IRH signatures that can significantly influence the characteristics of the tumor immune microenvironment (TIME) were selected using machine learning methods. The expression level of ICGs was significantly upregulated in GZMB+ CD8+ T-cells and tumor-associated macrophages (TAMs) in tumor tissues. TGFBI+ TAMs are a kind of blood-derived monocyte-derived M0-like TAM linked to hypoxia and a poor prognosis. IFI30+ M1-like TAMs participate in the process of immune-regulation and showed a role in the promotion of CD8+ T-cells and Type 1 T helper (Th1)/Th2 cells in the coexpression network, together with several IRLs, IRGs, and ICGs.ConclusionsCD16+ monocyte-derived IFI30+ TAMs participated in our coexpression network to regulate the TIME, showing the potential to be a novel immunotherapy target. The enrichment of M0-like TAMs was associated with a worse prognosis in the high-risk score group with IRH signatures. Remarkably, M0-like TAMs in tumor tissues overexpressed TGFBI and were associated with several well-known tumor-proliferation pathways.

Project description:BackgroundCervical cancer is the fourth most common cancer in women globally, and the main cause of the disease has been found to be ongoing HPV infection. Cervical cancer remains the primary cause of cancer-related death despite major improvements in screening and treatment approaches, especially in low- and middle-income nations. Therefore, it is crucial to investigate the tumor microenvironment in advanced cervical cancer in order to identify possible treatment targets.Materials and methodsIn order to better understand malignant cervical cancer epithelial cells (EPCs), this study used bulk RNA-seq data from UCSC in conjunction with single-cell RNA sequencing data from the ArrayExpress database. After putting quality control procedures into place, cell type identification and clustering analysis using the Seurat software were carried out. To clarify functional pathways, enrichment analysis and differential gene expression were carried out. The CIBERSORT and ESTIMATE R packages were used to evaluate the immune microenvironment characteristics, and univariate and multivariate Cox regression analyses were used to extract prognostic features. Furthermore, assessments of drug sensitivity and functional enrichment were carried out.ResultsEight cell types were identified, with EPCs showing high proliferative and stemness features. Five EPC subpopulations were defined, with C1 NNMT+ CAEPCs driving tumor differentiation. A NNMT CAEPCs Risk Score (NCRS) model was developed, revealing a correlation between elevated NCRS scores and adverse patient outcomes characterized by immune evasion. In vitro experiments validated that the prognostic gene PLOD2 significantly enhances proliferation, migration, and invasion of cervical cancer cells.ConclusionThis investigation delineated eight cell types and five subpopulations of malignant EPCs in cervical cancer, establishing the C1 NNMT+ CAEPCs as a crucial therapeutic target. The NCRS model demonstrated its prognostic capability, indicating that higher scores are associated with poorer clinical outcomes. The validation of PLOD2 as a prognostic gene highlights its therapeutic potential, underscoring the critical need for integrating immunotherapy and targeted treatment strategies to enhance diagnostic and therapeutic approaches in cervical cancer.

Dataset Information

Single-Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma.

Publications

Single-Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma.

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