Abstract
Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.
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Data availability
The raw scRNA-seq data of the SMC cohort are available in the European Genome-phenome Archive database (EGAS00001003779, EGAS00001003769). The raw scRNA-seq and bulk RNA-seq data of the KUL3 cohort are available in the ArrayExpress under the accession codes E-MTAB-8410 and E-MTAB-8412. Processed scRNA-seq and metadata for the SMC and KUL3 cohorts are available in the NCBI Gene Expression Omnibus (GEO) database under the accession codes GSE132465, GSE132257 and GSE144735. Clusters and gene expression data of the SMC cohort can be found on the User-friendly InteRface tool to Explore Cell Atlas (URECA) website (http://ureca-singlecell.kr). Other datasets referenced in the study are available from the GEO database under the accession codes GSE14028, GSE131907 and GSE81861.
Code availability
The code for the intercellular interaction map has been deposited with GitHub (https://github.com/SGI-CRC/scRNA-seq).
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Acknowledgements
This study was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science & ICT (grant no. NRF-2017M3A9A7050803), by the Belgian Federation against Cancer grant nos. 2018-127 and 2016-133 and by a grant from Fondation Roi-Baudouin. S.T. and S.V. are respectively supported by a Senior Clinical Investigator award and a postdoctoral fellowship of the Research Foundation—Flanders.
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H.-O.L., Y.H., H.E.E. and Y.B.C. analyzed and interpreted the data. V.P., B.V.B., J.V. and H.H. processed the tumors. S.V., J.-W.M., N.K., H.H.E., J.Q., B.B., D.L., P.T., T.L., M.A. and P.W. provided bioinformatics support. M.-H.J., G.D.H., W.C., H.-T.S. and J.-G.J. set up the server and analyzed the bulk data. Y.H. and G.K. constructed the visualization website. S.H.K. provided pathological examination. H.C.K., S.H.Y., W.Y.L., T.-Y.K., J.K.C. and Y.-J.K. interpreted the clinical data. I.B.H.T., B.R. and S.P. provided critical bioinformatics guidance. S.T. and W.-Y.P. conceived and supervised the study. H.-O.L., Y.H., H.E.E., Y.B.C., S.T. and W.-Y.P. wrote the manuscript with contributions and approval from all authors.
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Lee, HO., Hong, Y., Etlioglu, H.E. et al. Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat Genet 52, 594–603 (2020). https://doi.org/10.1038/s41588-020-0636-z
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DOI: https://doi.org/10.1038/s41588-020-0636-z
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