Dataset Information

A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

ABSTRACT: Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor cell composition, including phenotypic abnormalities and phenotype dominance. Relationship analyses between tumor and immune cells revealed characteristics of ecosystems related to immunosuppression and poor prognosis. High frequencies of PD-L1⁺ tumor-associated macrophages and exhausted T cells were found in high-grade ER⁺ and ER^- tumors. This large-scale, single-cell atlas deepens our understanding of breast tumor ecosystems and suggests that ecosystem-based patient classification will facilitate identification of individuals for precision medicine approaches targeting the tumor and its immunoenvironment.

SUBMITTER: Wagner J

PROVIDER: S-EPMC6526772 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

Wagner Johanna J Rapsomaniki Maria Anna MA Chevrier Stéphane S Anzeneder Tobias T Langwieder Claus C Dykgers August A Rees Martin M Ramaswamy Annette A Muenst Simone S Soysal Savas Deniz SD Jacobs Andrea A Windhager Jonas J Silina Karina K van den Broek Maries M Dedes Konstantin Johannes KJ Rodríguez Martínez Maria M Weber Walter Paul WP Bodenmiller Bernd B

Cell 20190411 5

Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor ...[more]

PMID: 30982598

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Project description:Background: The histological and molecular classification of breast cancer (BC) is being used in the clinical management of this disease. However, subtyping of BC based on the tumor immune microenvironment (TIME) remains insufficiently explored, although such investigation may provide new insights into intratumor heterogeneity in BC and potential clinical implications for BC immunotherapy. Methods: Based on the enrichment scores of 28 immune cell types, we performed clustering analysis of transcriptomic data to identify immune-specific subtypes of BC using six different datasets, including five bulk tumor datasets and one single-cell dataset. We further analyzed the molecular and clinical features of these subtypes. Results: Consistently in the six datasets, we identified three BC subtypes: BC-ImH, BC-ImM, and BC-ImL, which had high, medium, and low immune signature scores, respectively. BC-ImH displayed a significantly better survival prognosis than BC-ImL. Triple-negative BC (TNBC) and human epidermal growth factor receptor-2-positive (HER2+) BC were likely to have the highest proportion in BC-ImH and the lowest proportion in BC-ImL. In contrast, hormone receptor-positive (HR+) BC had the highest proportion in BC-ImL and the lowest proportion in BC-ImH. Furthermore, BC-ImH had the highest tumor mutation burden (TMB) and predicted neoantigens, while BC-ImL had the highest somatic copy number alteration (SCNA) scores. It is consistent with that TMB and SCNA correlate positively and negatively with anti-tumor immune response, respectively. TP53 had the highest mutation rate in BC-ImH and the lowest mutation rate in BC-ImL, supporting that TP53 mutations promote anti-tumor immune response in BC. In contrast, PIK3CA displayed the highest mutation rate in BC-ImM, while GATA3 had the highest mutation rate in BC-ImL. Besides immune pathways, many oncogenic pathways were upregulated in BC-ImH, including ErbB, MAPK, VEGF, and Wnt signaling pathways; the activities of these pathways correlated positively with immune signature scores in BC. Conclusions: The tumors with the strong immune response ("hot" tumors) have better clinical outcomes than the tumors with the weak immune response ("cold" tumors) in BC. TNBC and HER2+ BC are more immunogenic, while HR + BC is less immunogenic. Certain HER2+ or HR + BC patients could be propitious to immunotherapy in addition to TNBC.

Project description:The liver is unique in both its ability to maintain immune homeostasis and in its potential for immune tolerance following solid organ transplantation. Single-cell RNA sequencing (scRNA seq) is a powerful approach to generate highly dimensional transcriptome data to understand cellular phenotypes. However, when scRNA data is produced by different groups, with different data models, different standards, and samples processed in different ways, it can be challenging to draw meaningful conclusions from the aggregated data. The goal of this study was to establish a method to combine 'human liver' scRNA seq datasets by 1) characterizing the heterogeneity between studies and 2) using the meta-atlas to define the dominant phenotypes across immune cell subpopulations in healthy human liver. Publicly available scRNA seq data generated from liver samples obtained from a combined total of 17 patients and ~32,000 cells were analyzed. Liver-specific immune cells (CD45+) were extracted from each dataset, and immune cell subpopulations (myeloid cells, NK and T cells, plasma cells, and B cells) were examined using dimensionality reduction (UMAP), differential gene expression, and ingenuity pathway analysis. All datasets co-clustered, but cell proportions differed between studies. Gene expression correlation demonstrated similarity across all studies, and canonical pathways that differed between datasets were related to cell stress and oxidative phosphorylation rather than immune-related function. Next, a meta-atlas was generated via data integration and compared against PBMC data to define gene signatures for each hepatic immune subpopulation. This analysis defined key features of hepatic immune homeostasis, with decreased expression across immunologic pathways and enhancement of pathways involved with cell death. This method for meta-analysis of scRNA seq data provides a novel approach to broadly define the features of human liver immune homeostasis. Specific pathways and cellular phenotypes described in this human liver immune meta-atlas provide a critical reference point for further study of immune mediated disease processes within the liver.

Dataset Information

A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

Publications

A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

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