Spatially organized multicellular immune hubs in human colorectal cancer

作者：Karin Pelka, Matan Hofree, Jonathan Chen, Siranush Sarkizova, Joshua D. Pirl, Vjola Jorgji, Alborz Bejnood, Danielle Dionne, William Ge, Katherine Xu, Sherry Chao, Daniel R. Zollinger, David Lieb, Jason Reeves, Christopher A. Fuhrman, Margaret L. Hoang, Toni Delorey, Lan Nguyễn, Julia Waldman, Max Klapholz, Isaac Wakiro, Ofir Cohen, Julian J. 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 DelloStritto, Sarah Denning, Susannah Phillips, Emma K. Hill, Julia K. Meehan, Dennie T. Frederick, Tatyana Sharova, Abhay Kanodia, Ellen Todres, Judit Jané‐Valbuena, Moshe Biton, Benjamin Izar, Conner 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 · 发表于：Cell · 年份：2021 · DOI：10.1016/j.cell.2021.08.003 · 被引用次数：905 · 研究领域：Single-cell and spatial transcriptomics、T-cell and B-cell Immunology、Cancer Immunotherapy and Biomarkers

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.