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.
Competing Interest Statement
K.P., M.H., J.C., V.K., A.A., O.R, A.R., and N.H. are co-inventors on US Patent Application No. 16/995,425 relating to methods for predicting outcomes and treating colorectal cancer as described in the manuscript. A.J.A. is a Consultant for Oncorus, Inc., Arrakis Therapeutics, and Merck & Co., Inc., and receives research funding from Mirati Therapeutics; Deerfield, Inc.; Novo Ventures. R.B.C. is receiving consulting or speaking fees from Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Fog Pharma, Fount Therapeutics/Kinnate Biopharma, Genentech, Guardant Health, Ipsen, LOXO, Merrimack, Mirati Therapeutics, Natera, N-of-one/Qiagen, Novartis, nRichDx, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Fount Therapeutics/Kinnate Biopharma, nRichDx, and Revolution Medicines; and has received research funding from Asana, AstraZeneca, Lilly, and Sanofi. V.K.K.consults for Pfizer, GSK, Tizona Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Compass Therapeutics, Biocon, Syngene. G.M.B. has sponsored research agreements with Palleon Pharmaceuticals, Olink Proteomics, and Takeda Oncology. She served on scientific advisory boards for Novartis and Nektar Therapeutics. She received honoraria from Novartis. A.C.A. is a paid consultant for iTeos Therapeutics, and is a member of the SAB for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and ImmuneOncia, which have interests in cancer immunotherapy. A.C.A.'s interests were reviewed and managed by the Brigham and Women's Hospital and Partners Healthcare in accordance with their conflict of interest policies. M.G. receives research funding from Bristol Myers-Squibb, Merck and Servier. J.W.R., C.A.F., M.L.H. are employees of and stockholders for NanoString Technologies Inc., D.R.Z. is a former employee of NanoString Technologies Inc. B.I. is a consultant for Merck and Volastra Therapeutic. R.B. is an UptoDate Author. As.R. is an equity holder in Celsius Therapeutics and NucleAI. K.N. has research funding from Janssen, Revolution Medicines, Evergrande Group, Pharmavite; Advisory board: Seattle Genetics, BiomX; Consulting: X-Biotix Therapeutics; Research Funding: Bristol-Myers Squibb, Merck, Servier. B.E.J. is on the SA for Checkpoint Therapeutics. O.R.R. is a named inventor on several patents and patent applications filed by the Broad Institute in the area of single cell genomics. From October, 2020, O.R.R. is an employee of Genentech. A.R. is a founder of and equity holder in Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and was a scientific advisory board member for ThermoFisher Scientific, Syros Pharmaceuticals and Neogene Therapeutics until August 1, 2020. From August 1, 2020, A.R. is an employee of Genentech. A.R. is a named inventor on several patents and patent applications filed by the Broad Institute in the area of single cell and spatial genomics. N.H. holds equity in BioNTech and is an advisor for Related Sciences.
Footnotes
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