Speaker
Description
A growing tumour is an evolving system: during tumour development, cancer cells randomly acquire mutations that may provide them with a beneficial phenotype. However, such alterations can also give rise to neoantigens – novel cancer-specific peptides presented on the cell surface that trigger host immune responses. Successfully navigating interactions with the microenvironment and overcoming immune elimination is therefore a crucial step in cancer development. In recent work on colorectal cancer, we analysed the relative timing and evolutionary dynamics of subclones bearing immune-relevant alterations, observing a “Big Bang” pattern in which mutations acquired early in tumour growth shaped subsequent tumour-immune evolution \cite{Lakatos:2025aa}.
Here, we investigate under which biological and sampling regimes such patterns are expected – or not expected –; and how immunogenicity metrics or sequencing strategies capture various modes of tumour-immune co-evolution. Building on our previous stochastic branching process-based model of tumour evolution and neoantigen acquisition \cite{Lakatos:2020aa}, we simulate sequencing data from multi-region biopsies to explore the distribution of neoantigen burden and diversity under different levels of ongoing immune selection and immune escape prevalence. Our simulations span from near-neutral evolution to strong early immune pressure selecting for parallel escape, illustrating how distinct regimes manifest in sequencing data patterns.
Bibliography
@article{Lakatos:2020aa,
author = {Lakatos, Eszter and Williams, Marc J. and Schenck, Ryan O. and Cross, William C. H. and Househam, Jacob and Zapata, Luis and Werner, Benjamin and Gatenbee, Chandler and Robertson-Tessi, Mark and Barnes, Chris P. and Anderson, Alexander R. A. and Sottoriva, Andrea and Graham, Trevor A.},
date = {2020-10-01},
date-added = {2026-03-23 14:06:08 +0100},
date-modified = {2026-03-23 14:06:08 +0100},
doi = {10.1038/s41588-020-0687-1},
id = {Lakatos2020},
isbn = {1546-1718},
journal = {Nature Genetics},
number = {10},
pages = {1057--1066},
title = {Evolutionary dynamics of neoantigens in growing tumors},
url = {https://doi.org/10.1038/s41588-020-0687-1},
volume = {52},
year = {2020},
bdsk-url-1 = {https://doi.org/10.1038/s41588-020-0687-1}}
@article{Lakatos:2025aa,
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.},
author = {Lakatos, Eszter and Gunasri, Vinaya and Zapata, Luis and Househam, Jacob and Heide, Timon and Trahearn, Nicholas and Swinyard, Ottilie and Cisneros, Luis and Lynn, Claire and Mossner, Maximilian and Kimberley, Chris and Spiteri, Inmaculada and Cresswell, George D. and Llibre-Palomar, Gerard and Mitchison, Miriam and Maley, Carlo C. and Jansen, Marnix and Rodriguez-Justo, Manuel and Bridgewater, John and Baker, Ann-Marie and Sottoriva, Andrea and Graham, Trevor A.},
date = {2025-12-01},
date-added = {2026-03-23 14:05:15 +0100},
date-modified = {2026-03-23 14:05:15 +0100},
doi = {10.1038/s41588-025-02349-1},
id = {Lakatos2025},
isbn = {1546-1718},
journal = {Nature Genetics},
number = {12},
pages = {3039--3049},
title = {Epigenetically driven and early immune evasion in colorectal cancer evolution},
url = {https://doi.org/10.1038/s41588-025-02349-1},
volume = {57},
year = {2025},
bdsk-url-1 = {https://doi.org/10.1038/s41588-025-02349-1}}
