Immunosuppressive niche engineering at the onset of human colorectal cancer.
Date
2022-04-04Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Adenoma
Biological Evolution
Carcinoma
Colorectal Neoplasms
Humans
Immunotherapy
Research team
Evol Genomics & Modelling
Genomics & evolut dynam
Language
eng
Date accepted
2022-02-24
License start date
2022-04-04
Citation
Nature Communications, 2022, 13 (1), pp. 1798 -
Publisher
NATURE PORTFOLIO