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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
Cell | 2021

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.

Pubmed ID: 34450029 RIS Download

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R35 CA197735
  • Agency: NCI NIH HHS, United States
    Id: R00 CA259511
  • Agency: NCI NIH HHS, United States
    Id: K08 CA222663
  • Agency: NCI NIH HHS, United States
    Id: K08 CA218420
  • Agency: NIAID NIH HHS, United States
    Id: R56 AI137244
  • Agency: NCI NIH HHS, United States
    Id: R01 CA205406
  • Agency: NCI NIH HHS, United States
    Id: U2C CA233195
  • Agency: NCI NIH HHS, United States
    Id: R01 CA208756
  • Agency: NCI NIH HHS, United States
    Id: P50 CA127003
  • Agency: NCI NIH HHS, United States
    Id: T32 CA207021
  • Agency: NCI NIH HHS, United States
    Id: K99 CA259511
  • Agency: NCI NIH HHS, United States
    Id: U54 CA225088
  • Agency: NCI NIH HHS, United States
    Id: U01 CA224146
  • Agency: NHGRI NIH HHS, United States
    Id: T32 HG002295
  • Agency: NCI NIH HHS, United States
    Id: HHSN261201500003C
  • Agency: NCI NIH HHS, United States
    Id: R33 CA160344
  • Agency: NCI NIH HHS, United States
    Id: HHSN261201500003I
  • Agency: NCI NIH HHS, United States
    Id: U54 CA224068

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