Cancers from novel Pole mutant mouse models provide insights into polymerase-mediated hypermutagenesis and immune checkpoint blockade.

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into 3 groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultra-hypermutation and specific signatures. Furthermore, Pole-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in inter- and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE-driven tumors and valuable information for genetic counselling, surveillance, and immunotherapy for patients.