Spatially organized multicellular immune hubs in human colorectal cancer

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. [Display omitted] •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 Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors.