We identified 88 cell subsets across immune, stromal, and malignant cells and 204 associated gene expression programs. Here we developed a systematic approach to discover cell types, their underlying programs, and cellular communities based on single-cell RNA sequencing (scRNA-seq) profiles and applied it to study the distinguishing features of human MMRd and MMRp CRC. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks. 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. 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.
Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across 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. Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors.
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