Abstract
The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4+ T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers.
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Data availability
Raw sequencing reads of the single-cell RNA experiments have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-8107, E-MTAB-6149 and E-MTAB-6653. Based on SCope package,103 an interactive web server for scRNA-seq data visualisation, exploration and downloading of the count matrix is available at http://blueprint.lambrechtslab.org.
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Acknowledgements
We thank T. Van Brussel, R. Schepers, and E. Vanderheyden for their technical assistance. This work was supported by VIB TechWatch funding, Scientific Fund for Research-Flanders (FWO) grants to D. Lambrechts (G065615N), a Stichting tegen Kanker (STK) grant to D. Lambrechts (FAF-C/2016/876) and a VIB Grand Challenge grant to D. Lambrechts. The computational resources used in this work were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation and the Flemish Government, Department of Economy, Science and Innovation (EWI).
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J.Q. and D. Lambrechts. designed and supervised the study and wrote the manuscript; J.Q. and B.B. performed data analysis with significant contributions from P.B. and J.X.; I.V., A.S., S.T. and E.W. coordinated sample collection and clinical annotation with assistance from S.O., H.V., E.E., V.P., S.V., A.B., M.V.B., A.F. and G.F.; F.M.B., Y.V.H. and A.A. performed MILAN for melanoma samples. D. Laoui and B.T. contributed with critical data interpretation. All the authors have read the manuscript and provided useful comments.
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Qian, J., Olbrecht, S., Boeckx, B. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res 30, 745–762 (2020). https://doi.org/10.1038/s41422-020-0355-0
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DOI: https://doi.org/10.1038/s41422-020-0355-0
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