Spatially organized multicellular immune hubs in human colorectal cancer

TLDR

Immune responses to colorectal cancer vary, with mismatch repair‑deficient tumors showing stronger anti‑tumor immunity than mismatch repair‑proficient tumors. The study seeks to uncover the rules governing these variable immune responses by profiling cellular programs and identifying spatially organized immune‑malignant cell hubs. The authors performed single‑cell transcriptional profiling of 371,223 cells from 62 colorectal cancer patients and spatial profiling, analyzing 88 cell subsets and 204 gene expression programs to map transcriptional and spatial remodeling and to locate co‑varying programs across tumors. They identified a myeloid‑cell‑attracting hub at the tumor‑luminal interface linked to tissue damage and an MMRd‑enriched immune hub within the tumor where activated T cells, malignant cells, and myeloid cells express T‑cell‑attracting chemokines.

Abstract

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.