Epigenetically driven and early immune evasion in colorectal cancer evolution
Journal article, 2025
Immune system control is a principal hurdle in cancer evolution. The temporal dynamics of immune evasion remain incompletely characterized, and how immune-mediated selection interrelates with epigenome alteration is unclear. Here we infer the genome- and epigenome-driven evolutionary dynamics of tumor-immune coevolution within primary colorectal cancers (CRCs). We utilize a multiregion multiomic dataset of matched genome, transcriptome and chromatin accessibility profiling from 495 single glands (from 29 CRCs) supplemented with high-resolution spatially resolved neoantigen sequencing data and multiplexed imaging of the tumor microenvironment from 82 microbiopsies within 11 CRCs. Somatic chromatin accessibility alterations contribute to accessibility loss of antigen-presenting genes and silencing of neoantigens. Immune escape and exclusion occur at the outset of CRC formation, and later intratumoral differences in immuno-editing are negligible or exclusive to sites of invasion. Collectively, immune evasion in CRC follows a 'Big Bang' evolutionary pattern, whereby it is acquired close to transformation and defines subsequent cancer-immune evolution.
Author
Eszter Lakatos
University of Gothenburg
Chalmers, Mathematical Sciences, Applied Mathematics and Statistics
Vinaya Gunasri
Queen Mary University of London
University College London (UCL)
Luis Zapata
Institute of Cancer Research
Arizona State University
Jacob Househam
Institute of Cancer Research
Timon Heide
Human Technopole
Institute of Cancer Research
Nicholas Trahearn
University College London (UCL)
Institute of Cancer Research
Ottilie Swinyard
Queen Mary University of London
Luis Cisneros
Arizona State University
Claire Lynn
Institute of Cancer Research
Maximilian Mossner
Queen Mary University of London
Institute of Cancer Research
Chris Kimberley
Queen Mary University of London
Inmaculada Spiteri
Institute of Cancer Research
George D. Cresswell
Institute of Cancer Research
St. Anna Children's Cancer Research Institute (CCRI)
Gerard Llibre-Palomar
Queen Mary University of London
Miriam Mitchison
University College London (UCL)
Carlo C. Maley
Arizona State University
Marnix Jansen
University College London (UCL)
Manuel Rodriguez-Justo
University College London (UCL)
John Bridgewater
University College London (UCL)
Ann-Marie Baker
Institute of Cancer Research
Queen Mary University of London
Andrea Sottoriva
Institute of Cancer Research
Human Technopole
Trevor A. Graham
Queen Mary University of London
Institute of Cancer Research
Nature Genetics
1061-4036 (ISSN) 15461718 (eISSN)
Vol. 57 12 3039-3049Unravelling resistance evolution using liquid biopsies
Swedish Research Council (VR) (2024-04145), 2025-01-01 -- 2028-12-31.
Areas of Advance
Health Engineering
Subject Categories (SSIF 2025)
Cancer and Oncology
DOI
10.1038/s41588-025-02349-1
PubMed
41193656