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Spatially organized multicellular immune hubs in human colorectal cancer

Karin Pelka, Matan Hofree, Jonathan H. Chen, Siranush Sarkizova, Joshua D. Pirl, Vjola Jorgji, Alborz Bejnood, Danielle Dionne, William H. Ge, Katherine H. Xu, Sherry X. Chao, Daniel R. Zollinger, David J. Lieb, Jason W. Reeves, Christopher A. Fuhrman, Margaret L. Hoang, Toni Delorey, Lan T. Nguyen, Julia Waldman, Max Klapholz, Isaac Wakiro, Ofir Cohen, Julian Albers, Christopher S. Smillie, Michael S. Cuoco, Jingyi Wu, Mei-ju Su, Jason Yeung, Brinda Vijaykumar, Angela M. Magnuson, Natasha Asinovski, Tabea Moll, Max N. Goder-Reiser, Anise S. Applebaum, Lauren K. Brais, Laura K. DelloStritto, Sarah L. Denning, Susannah T. Phillips, Emma K. Hill, Julia K. Meehan, Dennie T. Frederick, Tatyana Sharova, Abhay Kanodia, Ellen Z. Todres, Judit Jané-Valbuena, Moshe Biton, Benjamin Izar, Conner D. Lambden, Thomas E. Clancy, Ronald Bleday, Nelya Melnitchouk, Jennifer Irani, Hiroko Kunitake, David L. Berger, Amitabh Srivastava, Jason L. Hornick, Shuji Ogino, Asaf Rotem, Sébastien Vigneau, Bruce E. Johnson, Ryan B. Corcoran, Arlene H. Sharpe, Vijay K. Kuchroo, Kimmie Ng, Marios Giannakis, Linda T. Nieman, Genevieve M. Boland, Andrew J. Aguirre, Ana C. Anderson, Orit Rozenblatt-Rosen, Aviv Regev, Nir Hacohen

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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Species: human
Number of cells: 371223
Number of downloads: 23
Study size: 14GB
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colorectal cancer