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

doi:10.1016/j.cell.2021.08.003

Spatially organized multicellular immune hubs in human colorectal cancer

Cell. 2021 Sep 2;184(18):4734-4752.e20. doi: 10.1016/j.cell.2021.08.003. Epub 2021 Aug 26.

Authors

Karin Pelka¹, Matan Hofree², Jonathan H Chen³, Siranush Sarkizova⁴, Joshua D Pirl⁴, Vjola Jorgji⁵, Alborz Bejnood², Danielle Dionne², William H Ge⁴, Katherine H Xu⁶, Sherry X Chao⁷, Daniel R Zollinger⁸, David J Lieb⁴, Jason W Reeves⁸, Christopher A Fuhrman⁸, Margaret L Hoang⁸, Toni Delorey², Lan T Nguyen², Julia Waldman², Max Klapholz⁹, Isaac Wakiro¹⁰, Ofir Cohen¹¹, Julian Albers⁴, Christopher S Smillie², Michael S Cuoco², Jingyi Wu¹⁰, Mei-Ju Su¹⁰, Jason Yeung¹⁰, Brinda Vijaykumar¹², Angela M Magnuson¹², Natasha Asinovski¹², Tabea Moll¹³, Max N Goder-Reiser¹³, Anise S Applebaum¹³, Lauren K Brais¹⁴, Laura K DelloStritto¹⁰, Sarah L Denning¹⁴, Susannah T Phillips¹³, Emma K Hill¹⁴, Julia K Meehan¹⁴, Dennie T Frederick¹³, Tatyana Sharova¹³, Abhay Kanodia¹⁰, Ellen Z Todres⁴, Judit Jané-Valbuena², Moshe Biton¹⁵, Benjamin Izar¹⁶, Conner D Lambden⁹, Thomas E Clancy¹⁷, Ronald Bleday¹⁷, Nelya Melnitchouk¹⁷, Jennifer Irani¹⁷, Hiroko Kunitake¹⁸, David L Berger¹⁸, Amitabh Srivastava¹⁹, Jason L Hornick¹⁹, Shuji Ogino²⁰, Asaf Rotem¹⁰, Sébastien Vigneau¹⁰, Bruce E Johnson²¹, Ryan B Corcoran²², Arlene H Sharpe²³, Vijay K Kuchroo⁹, Kimmie Ng²⁴, Marios Giannakis²⁵, Linda T Nieman⁶, Genevieve M Boland²⁶, Andrew J Aguirre²⁵, Ana C Anderson²⁷, Orit Rozenblatt-Rosen²⁸, Aviv Regev²⁹, Nir Hacohen³⁰

Affiliations

¹ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA.
² Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Pathology, MGH, Boston, MA, USA.
⁴ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
⁵ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Pathology, MGH, Boston, MA, USA.
⁶ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA.
⁷ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Biomedical Informatics, HMS, Boston, MA, USA.
⁸ NanoString Technologies Inc., Seattle, WA, USA.
⁹ Evergrande Center for Immunologic Diseases, HMS and Brigham and Women's Hospital (BWH), Boston, MA, USA.
¹⁰ Center for Cancer Genomics, Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA.
¹¹ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Center for Cancer Genomics, Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA; Department of Medical Oncology, DFCI, Boston, MA, USA.
¹² Department of Immunology, HMS, Boston, MA, USA.
¹³ Clinical Research Center, MGH, Boston, MA, USA.
¹⁴ Clinical Research Center, DFCI, Boston, MA, USA.
¹⁵ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Molecular Biology, MGH, Boston, MA, USA.
¹⁶ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Genomics, Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA; Department of Medical Oncology, DFCI, Boston, MA, USA.
¹⁷ Department of Surgery, BWH, Boston, MA, USA.
¹⁸ Department of Surgery, MGH, Boston, MA, USA.
¹⁹ Department of Pathology, BWH, Boston, MA, USA.
²⁰ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, BWH, Boston, MA, USA.
²¹ Center for Cancer Genomics, Department of Medical Oncology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA; Department of Medical Oncology, DFCI, Boston, MA, USA.
²² Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, HMS, Boston, MA, USA.
²³ Evergrande Center for Immunologic Diseases, HMS and Brigham and Women's Hospital (BWH), Boston, MA, USA; Department of Immunology, Blavatnik Institute, HMS, Boston, MA, USA.
²⁴ Department of Medical Oncology, DFCI, Boston, MA, USA.
²⁵ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medical Oncology, DFCI, Boston, MA, USA.
²⁶ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Surgery, MGH, Boston, MA, USA.
²⁷ Evergrande Center for Immunologic Diseases, HMS and Brigham and Women's Hospital (BWH), Boston, MA, USA. Electronic address: acanderson@bwh.harvard.edu.
²⁸ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: orit@broadinstitute.org.
²⁹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA. Electronic address: aviv.regev.sc@gmail.com.
³⁰ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Immunology, HMS, Boston, MA, USA. Electronic address: nhacohen@mgh.harvard.edu.

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.

Keywords: MSI; MSS; anti-tumor immunity; cell-cell interactions; colorectal cancer; mismatch repair-deficient; mismatch repair-proficient; scRNA-seq; spatial; tumor atlas.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Bone Morphogenetic Proteins / metabolism
Cancer-Associated Fibroblasts / metabolism
Cancer-Associated Fibroblasts / pathology
Cell Compartmentation
Cell Line, Tumor
Chemokines / metabolism
Cohort Studies
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology*
Colorectal Neoplasms / pathology*
DNA Mismatch Repair / genetics
Endothelial Cells / metabolism
Gene Expression Regulation, Neoplastic
Humans
Immunity
Inflammation / pathology
Monocytes / pathology
Myeloid Cells / pathology
Neutrophils / pathology
Stromal Cells / metabolism
T-Lymphocytes / metabolism
Transcription, Genetic

Substances

Bone Morphogenetic Proteins
Chemokines

Abstract

Publication types

MeSH terms

Substances

Grants and funding