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Publication Detail
Immunosuppressive niche engineering at the onset of human colorectal cancer
  • Publication Type:
    Journal article
  • Authors:
    Gatenbee CD, Baker AM, Schenck RO, Strobl M, West J, Neves MP, Hasan SY, Lakatos E, Martinez P, Cross WCH, Jansen M, Rodriguez-Justo M, Whelan CJ, Sottoriva A, Leedham S, Robertson-Tessi M, Graham TA, Anderson ARA
  • Publisher:
    Springer Science and Business Media LLC
  • Publication date:
    04/04/2022
  • Journal:
    Nature Communications
  • Volume:
    13
  • Article number:
    1798
  • Medium:
    Electronic
  • Status:
    Published
  • Country:
    England
  • PII:
    10.1038/s41467-022-29027-8
  • Language:
    English
  • Keywords:
    Applied mathematics, Colorectal cancer, Tumour immunology
  • Notes:
    This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Abstract
The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC.
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