Epigenetically driven and early immune evasion in colorectal cancer evolution
Eszter Lakatos, Vinaya Gunasri, Luís Zapata, Jacob Househam, Timon Heide, Nicholas Trahearn, Ottilie Swinyard, Luis Cisneros, Claire Lynn, Maximilian Mossner, Christopher Kimberley, Inmaculada Spiteri, George D. Cresswell, Gerard Llibre-Palomar, Miriam Mitchison, Carlo C. Maley, Marnix Jansen, Manuel Rodriguez‐Justo, John Bridgewater, Ann‐Marie Baker, Andrea Sottoriva, Trevor A. Graham
Abstract
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.