Title | Immunosuppressive niche engineering at the onset of human colorectal cancer |
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Type | Journal article |
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Authors | Chandler Gatenbee, Ann-Marie Baker, Ryan Schenck, Maximilian Strobl, Jeffrey West, Margarida P. Neves, Sara Yakub Hasan, Eszter Lakatos, Pierre Martinez, William C. H. Cross, Marnix Jansen, Manuel Rodriguez-Justo, Christopher Whelan, Andrea Sottoriva, Simon Leedham, Mark Robertson-Tessi, Trevor Graham and Alexander R.A. Anderson |
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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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Article number | 1798 |
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Journal | Nature Communications |
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Journal citation | 13 |
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ISSN | 2041-1723 |
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Year | 2022 |
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Publisher | Nature Publishing Group |
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Publisher's version | License CC BY 4.0 File Access Level Open (open metadata and files) |
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Digital Object Identifier (DOI) | https://doi.org/10.1038/s41467-022-29027-8 |
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Web address (URL) | http://dx.doi.org/10.1038/s41467-022-29027-8 |
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Publication dates |
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Published | 04 Apr 2022 |
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