B8 - Modeling Homopolymer Switching as a Model Mechanism for Adaptive Immune Evasion

Introduction: : Mismatch repair deficient (MMRd) cancer is associated with one of the lowest responses to cancer therapies among different cancer types. MMRd cancers are associated with high mutation rate and are subsequently enriched in neoantigen production[1]. Furthermore, cancers of this type tend to be highly aggressive while also being highly immunogenic. This deficiency can be acquired through somatic mutations or it can be inherited (for example, in Lynch Syndrome)[1]. Recently, it has been discovered that mutations on the MutS homolog 6 (MSH6) and MutS homolog 2 (MSH2) proteins that comprise the MutSa complex affect the ability of mismatch repair to successfully execute in MMRd cancer types[2]. Deleterious mutations on these proteins can drive mutations in the clone as a whole forward through insertion deletion (in/del) errors on the homopolymers of the proteins. Intriguingly, empirical analysis has identified that cancer clones can recover the original function of their homopolymers and thereby reverse the MMRd state following immune evasion[2]. While the connection between this switching mechanism and the evasion of immune detection is understood to a degree, the underlying biophysical dynamics that drive this mechanism forward and allow this switching are not well understood. Without this information, the interface of this mechanism with cancer therapies will remain unknown, thus culling the progression of these therapies.

Materials and

Methods: : Our overall objective in this work is to determine the underlying dynamics of this homopolymer switching mechanism and how the immune system interfaces with this switching mechanism. Model development and analysis utilizes discrete time stochastic process theory to track the time dynamics of the homopolymer mutations and the effect on the related protein’s functionality. The dynamical model characterizes the probability of switching mutations on the homopolymer and the effect of those mutations on the overall mutation rate of the cancer clone.

Results, Conclusions, and Discussions:: We will have a theoretical understanding of the mechanism that drives the homopolymer switching. We develop a stochastic framework and, using this framework, we demonstrate that stochastic mutational switching can explain the dynamics of tumor immune evasion and reversion of the MMRd state following immune escape. We anticipate that this model can in the future be generalized to describe a broader class of adaptive immune evasion mechanisms in cancer.

Acknowledgements and/or References (Optional):: [1]Giovanni Germano, Nabil Amirouchene-Angelozzi, Giuseppe Rospo, Alberto Bardelli; The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers. Cancer Discov 1 December 2018; 8 (12): 1518–1528. https://doi.org/10.1158/2159-8290.CD-18-0150
[2] Kayhanian, H., Cross, W., van der Horst, S.E.M. et al. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer. Nat Genet 56, 1420–1433 (2024). https://doi.org/10.1038/s41588-024-01777-9