Multicellular immune hubs and their organization in MMRd and MMRp colorectal cancer

K. Pelka, M. Hofree, J. Chen, S. Sarkizova, J.D. Pirl, V. Jorgji, A. Bejnood, D. Dionne, W.H. Ge, K.H. Xu, S.X. Chao, D.R. Zollinger, D.J. Lieb, J.W. Reeves, C.A. Fuhrman, M.L. Hoang, T. Delorey, L.T. Nguyen, J. Waldman, M. KlapholzI. Wakiro, O. Cohen, C.S. Smillie, M.S. Cuoco, J. Wu, M.-J. Su, J. Yeung, B. Vijaykumar, A.M. Magnuson, N. Asinovski, T. Moll, M.N. Goder-Reiser, A.S. Applebaum, L.K. Brais, L.K. DelloStritto, S.L. Denning, S.T. Phillips, E.K. Hill, J.K. Meehan, D.T. Frederick, T. Sharova, A. Kanodia, E.Z. Todres, J. Jané-Valbuena, M. Biton, B. Izar, C.D. Lambden, T.E. Clancy, R. Bleday, N. Melnitchouk, J. Irani, H. Kunitake, D.L. Berger, A. Srivastava, J.L. Hornick, S. Ogino, A. Rotem, S. Vigneau, B.E. Johnson, R.B. Corcoran, A.H. Sharpe, V.K. Kuchroo, K. Ng, M. Giannakis, L.T. Nieman, G.M. Boland, A.J. Aguirre, A.C. Anderson, O. Rozenblatt-Rosen, A. Regev, N. Hacohen

Research output: Working paper/preprintPreprint

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 patients. 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 patient tumors 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 thus reveal the logic underlying spatially organized immune-malignant cell networks. The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Original languageEnglish
DOIs
StatePublished - 2021

Publication series

NamebioRxiv
PublisherbioRxiv
ISSN (Print)2692-8205

Bibliographical note

Export Date: 27 November 2022

Correspondence Address: Anderson, A.C.; Evergrande Center for Immunologic Diseases, United States; email: acanderson@bwh.harvard.edu

Correspondence Address: Rozenblatt-Rosen, O.; Klarman Cell Observatory, United States; email: orit@broadinstitute.org

Correspondence Address: Regev, A.; Klarman Cell Observatory, United States; email: aregev@broadinstitute.org

Correspondence Address: Hacohen, N.; Broad Institute of Massachusetts Institute of Technology (MIT) and HarvardUnited States; email: nhacohen@mgh.harvard.edu

Keywords

  • Anti-tumor immunity
  • Cell-cell interactions
  • Colorectal cancer
  • Mismatch repair-deficient
  • Mismatch repair-proficient
  • MSI
  • MSS
  • ScRNA-seq
  • Spatial
  • cancer biology

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