Genetic instability as a driver for immune surveillance

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• dc.contributor.author Aguadé Gorgorió, Guim, 1991-
• dc.contributor.author Solé Vicente, Ricard, 1962-
• dc.date.accessioned 2020-01-09T08:57:47Z
• dc.date.available 2020-01-09T08:57:47Z
• dc.date.issued 2019
• dc.description.abstract Background: Genetic instability is known to relate with carcinogenesis by providing tumors with a mechanism for fast adaptation. However, mounting evidence also indicates causal relation between genetic instability and improved cancer prognosis resulting from efficient immune response. Highly unstable tumors seem to accumulate mutational burdens that result in dynamical landscapes of neoantigen production, eventually inducing acute immune recognition. How are tumor instability and enhanced immune response related? An important step towards future developments involving combined therapies would benefit from unraveling this connection. Methods: In this paper we present a minimal mathematical model to describe the ecological interactions that couple tumor adaptation and immune recognition while making use of available experimental estimates of relevant parameters. The possible evolutionary trade-offs associated to both cancer replication and T cell response are analysed, and the roles of mutational load and immune activation in governing prognosis are studied. Results: Modeling and available data indicate that cancer-clearance states become attainable when both mutational load and immune migration are enhanced. Furthermore, the model predicts the presence of well-defined transitions towards tumor control and eradication after increases in genetic instability numerically consistent with recent experiments of tumor control after Mismatch Repair knockout in mice. Conclusions: These two main results indicate a potential role of genetic instability as a driver of transitions towards immune control of tumors, as well as the effectiveness of increasing mutational loads prior to adoptive cell therapies. This mathematical framework is therefore a quantitative step towards predicting the outcomes of combined therapies where genetic instability might play a key role.
• dc.description.sponsorship This work has been supported by the Botín-Foundation by Banco Santander through its Santander Universities Global Division, a MINECO grant FIS2015-67616-P (MINECO/FEDER, UE) fellowship, an AGAUR grant 2018 by the Universities and Research Secretariat of the Ministry of Business and Knowledge of the Generalitat de Catalunya and the European Social Fund and by the Santa Fe Institute.
• dc.format.mimetype application/pdf
• dc.identifier.citation Aguadé-Gorgorió G, Solé R. Genetic instability as a driver for immune surveillance. J Immunother Cancer. 2019;7(1):345. DOI: 10.1186/s40425-019-0795-6
• dc.identifier.doi http://dx.doi.org/10.1186/s40425-019-0795-6
• dc.identifier.issn 2051-1426
• dc.identifier.uri http://hdl.handle.net/10230/43245
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Journal for ImmunoTherapy of Cancer. 2019;7(1):345
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/FIS2015-67616-P
• dc.rights © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Combination therapies
• dc.subject.keyword Genetic instability
• dc.subject.keyword Immune surveillance
• dc.subject.keyword Mismatch repair
• dc.subject.keyword Neoantigen load
• dc.title Genetic instability as a driver for immune surveillance
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion