期刊
CELL
卷 184, 期 18, 页码 4734-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.08.003
关键词
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资金
- Evergrande Center for Immunologic Diseases at BWH and HMS
- Klarman Cell Observatory
- HHMI
- NIH/NCI [R01 CA208756, K99CA259511, T32CA207021, K08 CA218420-02, P50 CA127003, U01 CA224146, R01CA205406]
- Arthur, Sandra, and Sarah Irving Fund for Gastrointestinal Immuno-Oncology
- NCI, NIH Task Order [HHSN261100039, HHSN261201500003I]
- HTAPP consortium and NIH HTAN (Human Tumor Atlas Network)
- DFG
- SU2C Peggy Prescott Early Career Scientist Award [PA-6146]
- SU2C Phillip A. Sharp Award [SU2C-AACR-PS-32]
- BroadIgnite
- Doris Duke Charitable Foundation
- Pancreatic Cancer Action Network
- NIH [R35 CA197735, K08CA222663, U54CA225088]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- CUMC Louis V. Gerstner, Jr. Scholars Program
- CUMC Velocity Fellow Program
- DOD [CA160344]
- Project P Fund
- SU2C Colorectal Cancer Dream Team Translational Research Grant [SU2C-AACR-DT22-17]
- [U54 CA224068]
By analyzing the transcriptional profiles of cells in tumors, differences in immune responses between mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors were identified, as well as the logic behind the interaction of malignant and immune cells discovered within tumors.
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.
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