Dataset Information

Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer.

ABSTRACT: Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an integrated combination of mass cytometry and imaging mass cytometry was used to analyze tumor cells, immune cells, and TME spatial characteristics of 44 MIBC patients. We detected tumor and immune cell clusters with abnormal phenotypes. In particular, we identified a previously overlooked cancer stem-like cell cluster (ALDH+PD-L1+ER-β-) that was strongly associated with poor prognosis. We elucidated the different spatial architectures of immune cells (excluded, infiltrated, and deserted) and tumor-associated collagens (curved, stretched, directionally distributed, and chaotic) in the MIBC TME. The present study is the first to provide in-depth insight into the complexity of the MIBC TME at the single-cell level. Our results will improve the general understanding of the heterogeneous characteristics of MIBC, potentially facilitating patient stratification and personalized therapy.

SUBMITTER: Feng C

PROVIDER: S-EPMC8582554 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer.

Feng Chao C Wang Xi X Tao Yuting Y Xie Yuanliang Y Lai Zhiyong Z Li Zhijian Z Hu Jiaxin J Tang Shaomei S Pan Lixin L He Liangyu L Wang Qiuyan Q Li Tianyu T Mo Zengnan Z

Cancers 20211029 21

Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an integrated combination of mass cytometry and imaging mass cytometry was used to analyze tumor cells, immune cells, and TME spatial characteristics of 44 MIBC patients. We detected tum ...[more]

PMID: 34771607

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Project description:Osteosarcoma (OS), which occurs most commonly in adolescents, is associated with a high degree of malignancy and poor prognosis. In order to develop an accurate treatment for OS, a deeper understanding of its complex tumor microenvironment (TME) is required. In the present study, tissues were isolated from six patients with OS, and then subjected to single-cell RNA sequencing (scRNA-seq) using a 10× Genomics platform. Multiplex immunofluorescence staining was subsequently used to validate the subsets identified by scRNA-seq. ScRNA-seq of six patients with OS was performed prior to neoadjuvant chemotherapy, and data were obtained on 29,278 cells. A total of nine major cell types were identified, and the single-cell transcriptional map of OS was subsequently revealed. Identified osteoblastic OS cells were divided into five subsets, and the subsets of those osteoblastic OS cells with significant prognostic correlation were determined using a deconvolution algorithm. Thereby, different transcription patterns in the cellular subtypes of osteoblastic OS cells were reported, and key transcription factors associated with survival prognosis were identified. Furthermore, the regulation of osteolysis by osteoblastic OS cells via receptor activator of nuclear factor kappa-B ligand was revealed. Furthermore, the role of osteoblastic OS cells in regulating angiogenesis through vascular endothelial growth factor-A was revealed. C3_TXNIP+ macrophages and C5_IFIT1+ macrophages were found to regulate regulatory T cells and participate in CD8+ T cell exhaustion, illustrating the possibility of immunotherapy that could target CD8+ T cells and macrophages. Our findings here show that the role of C1_osteoblastic OS cells in OS is to promote osteolysis and angiogenesis, and this is associated with survival prognosis. In addition, T cell depletion is an important feature of OS. More importantly, the present study provided a valuable resource for the in-depth study of the heterogeneity of the OS TME.

Project description:Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC). Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint-relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy. Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p < 0.001). CD8+ T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%). Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.

Dataset Information

Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer.

Publications

Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer.

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