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Evolutionary dynamics of neoantigens in growing tumours

View ORCID ProfileEszter Lakatos, View ORCID ProfileMarc J. Williams, View ORCID ProfileRyan O. Schenck, View ORCID ProfileWilliam C. H. Cross, View ORCID ProfileJacob Househam, View ORCID ProfileBenjamin Werner, View ORCID ProfileChandler Gatenbee, View ORCID ProfileMark Robertson-Tessi, View ORCID ProfileChris P. Barnes, View ORCID ProfileAlexander R. A. Anderson, View ORCID ProfileAndrea Sottoriva, View ORCID ProfileTrevor A. Graham
doi: https://doi.org/10.1101/536433
Eszter Lakatos
1Evolution and Cancer Laboratory, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Marc J. Williams
1Evolution and Cancer Laboratory, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Ryan O. Schenck
2Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
3Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
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William C. H. Cross
1Evolution and Cancer Laboratory, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Jacob Househam
1Evolution and Cancer Laboratory, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Benjamin Werner
4Evolutionary Genomics & Modelling Lab, Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
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Chandler Gatenbee
2Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Mark Robertson-Tessi
2Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Chris P. Barnes
5Department of Cell and Developmental Biology, University College London, London, UK
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Alexander R. A. Anderson
2Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Andrea Sottoriva
4Evolutionary Genomics & Modelling Lab, Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
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  • For correspondence: andrea.sottoriva@icr.ac.uk t.graham@qmul.ac.uk
Trevor A. Graham
1Evolution and Cancer Laboratory, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • For correspondence: andrea.sottoriva@icr.ac.uk t.graham@qmul.ac.uk
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ABSTRACT

Cancer evolution is driven by the acquisition of somatic mutations that provide cells with a beneficial phenotype in a changing microenvironment. However, mutations that give rise to neoantigens, novel cancer–specific peptides that elicit an immune response, are likely to be disadvantageous. Here we show how the clonal structure and immunogenotype of growing tumours is shaped by negative selection in response to neoantigenic mutations. We construct a mathematical model of neoantigen evolution in a growing tumour, and verify the model using genomic sequencing data. The model predicts that, in the absence of active immune escape mechanisms, tumours either evolve clonal neoantigens (antigen– ‘hot’), or have no clonally– expanded neoantigens at all (antigen– ‘cold’), whereas antigen– ‘warm’ tumours (with high frequency subclonal neoantigens) form only following the evolution of immune evasion. Counterintuitively, strong negative selection for neoantigens during tumour formation leads to an increased number of antigen– warm or – hot tumours, as a consequence of selective pressure for immune escape. Further, we show that the clone size distribution under negative selection is effectively– neutral, and moreover, that stronger negative selection paradoxically leads to more neutral– like dynamics. Analysis of antigen clone sizes and immune escape in colorectal cancer exome sequencing data confirms these results. Overall, we provide and verify a mathematical framework to understand the evolutionary dynamics and clonality of neoantigens in human cancers that may inform patient– specific immunotherapy decision– making.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 31, 2019.
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Evolutionary dynamics of neoantigens in growing tumours
Eszter Lakatos, Marc J. Williams, Ryan O. Schenck, William C. H. Cross, Jacob Househam, Benjamin Werner, Chandler Gatenbee, Mark Robertson-Tessi, Chris P. Barnes, Alexander R. A. Anderson, Andrea Sottoriva, Trevor A. Graham
bioRxiv 536433; doi: https://doi.org/10.1101/536433
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Evolutionary dynamics of neoantigens in growing tumours
Eszter Lakatos, Marc J. Williams, Ryan O. Schenck, William C. H. Cross, Jacob Househam, Benjamin Werner, Chandler Gatenbee, Mark Robertson-Tessi, Chris P. Barnes, Alexander R. A. Anderson, Andrea Sottoriva, Trevor A. Graham
bioRxiv 536433; doi: https://doi.org/10.1101/536433

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