Immunosuppressive niche engineering at the onset of human colorectal cancer.
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ICR Authors
Authors
Gatenbee, CD
Baker, A-M
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
Baker, A-M
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
Document Type
Journal Article
Date
2022-04-04
Date Accepted
2022-02-24
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.
Citation
Nature Communications, 2022, 13 (1), pp. 1798 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Evol Genomics & Modelling
Genomics & evolut dynam
Genomics & evolut dynam