Genetic instability as a driver for immune surveillance

Abstract

Abstract * BackgroundGenetic 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. * MethodsIn 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. * ResultsModeling 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. * ConclusionsThese 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.

Keywords

• Genetic instability
• Neoantigen load
• Mismatch repair
• Immune surveillance
• Combination therapies