Cell
Volume 184, Issue 18, 2 September 2021, Pages 4734-4752.e20
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Article
Spatially organized multicellular immune hubs in human colorectal cancer

https://doi.org/10.1016/j.cell.2021.08.003Get rights and content
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open access

Highlights

  • A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC

  • Co-variation of single-cell transcriptional programs across specimens predicts immune hubs

  • A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC

  • CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC

Summary

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Keywords

colorectal cancer
anti-tumor immunity
mismatch repair-deficient
mismatch repair-proficient
MSS
MSI
spatial
scRNA-seq
cell-cell interactions
tumor atlas

Data and code availability

Sequencing data of de-identified human subject specimens have been deposited at dbGaP: phs002407.v1.p1; expression transcript count matrices at GEO: GSE178341. Additional resources for exploring the data are available at our supplemental web page (https://broad.io/crchubs) and the Broad Institute’s Single Cell Portal (https://singlecell.broadinstitute.org/single_cell/study/SCP1162). Accession numbers and links to web pages are also listed in the Key resources table.

The principal analysis code used to analyze data and generate the results presented here has been deposited at github (https://github.com/matanhofree/crc-immune-hubs). The github link is also listed in the key resources table.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

20

Present address: Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA, USA

21

Present address: Columbia Center for Translational Immunology, New York, NY, USA

22

Present address: Columbia University Medical Center, Division of Hematology and Oncology, New York, NY, USA

23

Present address: Program for Mathematical Genomics, Columbia University, New York, NY, USA

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Present address: Genentech, 1 DNA Way, South San Francisco, CA, USA

25

These authors contributed equally

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These authors contributed equally

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Lead contact