Epigenetically driven and early immune evasion in colorectal cancer evolution
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.
Authors
- Inmaculada Spiteri (ORCID: https://orcid.org/0000-0002-1097-8972)
- Manuel Rodriguez‐Justo (ORCID: https://orcid.org/0000-0001-5007-1761)
- Nicholas Trahearn (ORCID: https://orcid.org/0000-0002-8596-0996)
- Jacob Househam (ORCID: https://orcid.org/0000-0003-3199-336X)
- Trevor A. Graham (ORCID: https://orcid.org/0000-0001-9582-1597)
- Andrea Sottoriva (ORCID: https://orcid.org/0000-0001-6709-9533)
- Ann‐Marie Baker (ORCID: https://orcid.org/0000-0001-8905-9137)
- Timon Heide (ORCID: https://orcid.org/0000-0002-1386-7469)
- George D. Cresswell (ORCID: https://orcid.org/0000-0003-3303-068X)
- Luis Cisneros (ORCID: https://orcid.org/0000-0002-7890-1269)
- Carlo C. Maley (ORCID: https://orcid.org/0000-0002-0745-7076)
- Vinaya Gunasri (ORCID: https://orcid.org/0000-0002-9292-6470)
- Eszter Lakatos (ORCID: https://orcid.org/0000-0002-7221-6850)
- Christopher Kimberley (ORCID: https://orcid.org/0000-0002-9720-4434)
- Miriam Mitchison (ORCID: https://orcid.org/0000-0003-2520-2744)
- Maximilian Mossner (ORCID: https://orcid.org/0000-0001-9751-3803)
- Marnix Jansen (ORCID: https://orcid.org/0000-0003-0645-564X)
- Luís Zapata (ORCID: https://orcid.org/0000-0002-1386-2019)
- John A. Bridgewater (ORCID: https://orcid.org/0000-0001-9186-1604)
- Ottilie Swinyard (ORCID: https://orcid.org/0000-0001-8474-8865)
- Claire Lynn (ORCID: https://orcid.org/0000-0002-2630-4075)
- Gerard Llibre-Palomar (ORCID: https://orcid.org/0000-0002-4741-3473)
Institutions
- University College London Hospitals NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Queen Mary University of London (GB)
- Human Technopole (IT)
- St Anna Children's Hospital (AT)
- CRUK Lung Cancer Centre of Excellence (GB)
- St. Anna Children's Cancer Research Institute
- University College London (GB)
- Arizona State University (US)
- Chalmers University of Technology (SE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1038/s41588-025-02349-1
- Citations
- 3
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Wellcome Trust
- Vetenskapsrådet
- National Institutes of Health
- Japan Society for the Promotion of Science