Mutation Rate Evolution Drives Immune Escape In Mismatch Repair-Deficient Cancer

Abstract

Mutation rate optimisation drives evolution and immune evasion of bacteria and lentiviral strains, including HIV. Whether evolving cancer lineages similarly adapt mutation rates to increase tumour cell fitness is unknown. Here, by mapping the clonal topography of mismatch repair-deficient (MMRd) colorectal cancer, we show that genomic MMRd mutability co-evolves with neoantigen selection to drive intratumour diversification and immune escape. Mechanistically, we find that microsatellite instability modulates subclonal DNA repair by toggling two hypermutable mononucleotide homopolymer runs in the mismatch repair genes MSH6 and MSH3 (C8 and A8, respectively) through stochastic frameshift switching. Spontaneous mutation and reversion at these evolvability switches modulates subclonal mutation rate, mutation bias, and clonal HLA diversity during MMRd cancer evolution. Combined experimental and simulation studies demonstrate that subclonal immune selection favours incremental MMR mutations. MMRd cancers thus fuel intratumour heterogeneity by adapting subclonal mutation rate and mutation bias to immune selection, revealing a conserved co-evolutionary arms race between neoantigen selection and adaptive genomic mutability. Our work reveals layers of mutational complexity and microsatellite biology in MMRd cancer evolution previously hidden in bulk analyses.

Spontaneous Complete Regression of Colon Cancer Liver Metastases in a Lung Transplant Patient: A Case Report

“…With the unexpected additional loss of expression in MSH6 in the liver metastases, in contrast to the primary tumor, the liver metastases could have contained more immunogenic neoantigens than the primary tumor. Intratumoral heterogeneity, with an additional loss of expression in MSH6 in the liver metastases, can be the result of the manner of subclonal immune selection in dMMR tumors [ 25 ].…”

Frequency-dependent selection of neoantigens fosters tumor immune escape and predicts immunotherapy response

“…This finding is intriguing because the pattern of neoantigens accumulation under NFDS resembles subclonal immune escape. It is widely accepted that tumor immune escape is achieved through specific genomic mutations in the genome 9,[40][41][42] . However, our results suggest that the specific interactions between tumor cells and the immune microenvironment confer immune-escape-like evolutionary dynamics.…”

“…Parameters were chosen to represent different tumor-immune environments and literatures was reviewed to estimate parameter values in our model. The following parameters were used in all simulations: b = 0.5 65,66 , b 0 ¼ 0:4, μ ¼ 5, p ¼ 0:1, p e ¼ 10 À4 (probability of immune escape, if applicable) 9,42 . For the analyses where cells and tumors were classified as immunogenic or non-immunogenic, the cell and tumor immunogenicity thresholds c 1 ¼ 0:5 and c 2 ¼ 0:5 were used 9 , unless otherwise stated.…”