A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling

AbstractBackgroundImmunotherapy has revolutionized cancer therapy. However, responses are not universal. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, how different tumors shape their tumor microenvironment remains a critical unsolved problem. A deeper insight into the molecular characteristics of inflamed tumor microenvironment may be needed.Materials and methodsHere, based on single-cell RNA sequencing technology and TCGA pan-cancer cohort, we investigated multi-omics molecular features of tumor microenvironment phenotypes. Based on single-cell RNA-seq analysis, we classified pan-cancer tumor samples into inflamed or non-inflamed tumor and identified molecular features of these tumors. Analysis of integrating identified gene signatures with a drug-genomic perturbation database identified multiple drugs which may be helpful for converting non-inflamed tumors to inflamed tumors.ResultsOur results revealed several inflamed/non-inflamed tumor microenvironments-specific molecular characteristics. For example, inflamed tumors highly expressed miR-650 and lncRNA including MIR155HG and LINC00426, these tumors showed activated cytokines-related signaling pathways. Interestingly, non-inflamed tumors tended to express several genes related to neurogenesis. Multi-omics analysis demonstrated the neuro phenotype transformation may be induced by hypomethylated promoters of these genes and down-regulated miR-650. Drug discovery analysis revealed histone deacetylase inhibitors may be a potential choice for helping favorable tumor microenvironment phenotype transformation and aiding current immunotherapy.ConclusionOur results provide a comprehensive molecular-level understanding of tumor cell-immune cell interaction and may have profound clinical implications.

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Single-Cell Profiling to Explore Immunological Heterogeneity of Tumor Microenvironment in Breast Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.643692 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiao Yuan ◽

Jinxi Wang ◽

Yixuan Huang ◽

Dangang Shangguan ◽

Peng Zhang

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Single Cell ◽

Immune Cells ◽

Critical Role ◽

Therapy Resistance ◽

Spatial Profiling ◽

Wide Range ◽

Single Cell Profiling ◽

Immunological Heterogeneity

Immune infiltrates in the tumor microenvironment (TME) of breast cancer (BRCA) have been shown to play a critical role in tumorigenesis, progression, invasion, and therapy resistance, and thereby will affect the clinical outcomes of BRCA patients. However, a wide range of intratumoral heterogeneity shaped by the tumor cells and immune cells in the surrounding microenvironment is a major obstacle in understanding and treating BRCA. Recent progress in single-cell technologies such as single-cell RNA sequencing (scRNA-seq), mass cytometry, and digital spatial profiling has enabled the detailed characterization of intratumoral immune cells and vastly improved our understanding of less-defined cell subsets in the tumor immune environment. By measuring transcriptomes or proteomics at the single-cell level, it provides an unprecedented view of the cellular architecture consist of phenotypical and functional diversities of tumor-infiltrating immune cells. In this review, we focus on landmark studies of single-cell profiling of immunological heterogeneity in the TME, and discuss its clinical applications, translational outlook, and limitations in breast cancer studies.

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