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Immunosuppressive niche engineering at the onset of human colorectal cancer

Author

Listed:
  • Chandler D. Gatenbee

    (H. Lee Moffitt Cancer Center & Research Institute)

  • Ann-Marie Baker

    (Barts Cancer Institute, Queen Mary University of London)

  • Ryan O. Schenck

    (H. Lee Moffitt Cancer Center & Research Institute
    University of Oxford)

  • Maximilian Strobl

    (H. Lee Moffitt Cancer Center & Research Institute)

  • Jeffrey West

    (H. Lee Moffitt Cancer Center & Research Institute)

  • Margarida P. Neves

    (Barts Cancer Institute, Queen Mary University of London)

  • Sara Yakub Hasan

    (Barts Cancer Institute, Queen Mary University of London)

  • Eszter Lakatos

    (Barts Cancer Institute, Queen Mary University of London)

  • Pierre Martinez

    (Barts Cancer Institute, Queen Mary University of London
    Lyon Cancer Institute)

  • William C. H. Cross

    (Barts Cancer Institute, Queen Mary University of London)

  • Marnix Jansen

    (University College London Hospital)

  • Manuel Rodriguez-Justo

    (University College London Hospital)

  • Christopher J. Whelan

    (H. Lee Moffitt Cancer Center & Research Institute
    University of Illinois at Chicago)

  • Andrea Sottoriva

    (Institute of Cancer Research)

  • Simon Leedham

    (University of Oxford)

  • Mark Robertson-Tessi

    (H. Lee Moffitt Cancer Center & Research Institute)

  • Trevor A. Graham

    (Barts Cancer Institute, Queen Mary University of London)

  • Alexander R. A. Anderson

    (H. Lee Moffitt Cancer Center & Research Institute)

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.

Suggested Citation

  • Chandler D. Gatenbee & Ann-Marie Baker & Ryan O. Schenck & Maximilian Strobl & Jeffrey West & Margarida P. Neves & Sara Yakub Hasan & Eszter Lakatos & Pierre Martinez & William C. H. Cross & Marnix Ja, 2022. "Immunosuppressive niche engineering at the onset of human colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29027-8
    DOI: 10.1038/s41467-022-29027-8
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