Pole D272A E274A mice carry D272A and E274A mutations in the polymerase (DNA directed), epsilon Pole gene. Pole and polymerase (DNA directed), delta 1, catalytic subunit (Pold1) have 3'-5' proofreading exonuclease activity that correct errors arising during DNA replication. Mutations in the exonuclease domains of these genes disable their proofreading function essential for correcting DNA replication errors and are associated with increased cancer incidence, elevated tumor mutation burden (TMB), and response to immune checkpoint blockade (ICB). Immune checkpoint blockade has been used as a treatment for multiple cancer types. It involves the use of antibodies that target T cell co-receptors, yet only a subset of patients respond well since ICB therapy only has a high response rate to tumors with high TMB. Pole D272A/D272A mice carry mutations in the endonuclease domain of POLE, creating a spontaneous proofreading mutation, and they exhibit high mutation burdens that are inherent to many human cancers. They exhibit mainly thymic and splenic lymphomas, and intestinal tumors and sarcomas. Exome sequencing of these tumors from this mouse model reveals a highly variable but elevated TMB with mutational signatures similar to that seen in Pole mutant human cancers. Treatment of this mouse model with ICB (anti-PD1 antibody) earlier and prior to the appearance of obvious tumors delays cancer onset leading to improved survival, suggesting the use of ICB in high-risk settings for cancer prevention. Homozygous Pole D272A/D272A mice are viable and fertile with a median survival of 494 days, with tumors evident starting around 200 days of age. The progeny from the homozygous animals were not used further for breeding to avoid the accumulation of mutations over generations. Heterozygous Pole D272A E274A mice rarely show a cancer phenotype, and their lifespan is comparable to wild type mice. Of note, the donating investigator made a panel of mice useful for studying the response of immune checkpoint blockade to elevated tumor mutation burden: Pold1 D400A mice are available as Stock No. <a href="https://www.jax.org/strain/040149">040149</a> Pole D272A E274A mice are available as Stock No. <a href="https://www.jax.org/strain/040150">040150</a> Pole L424V mice are available as Stock No. <a href="https://www.jax.org/strain/040151">040151</a> LSL-Pole V411L are cre-inducible and are available as Stock No. <a href="https://www.jax.org/strain/040152">040152</a> These mice were bred to KP mice (LSL-Kras G12D/+ p53 flox/flox) (Stock No. <a href="https://www.jax.org/strain/032435">032435</a>) where, after cre-induction, the oncogenic KrasG12D/+ allele is activated and Trp53 tumor suppressor gene is deleted. After intranasal delivery of adeno-Cre virus, these mice showed no difference in survival or lung weight at 12 weeks of age, but they did show a moderately increased mutation burden. Single cell passaging of tumor derived cell lines from these models modestly increased mutation burden and immunogenicity, leading to tumor immune rejection.

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Pole D272A E274A mice carry D272A and E274A mutations in the Pole gene. This mouse line may be useful when studying the response of immune checkpoint blockade to elevated tumor mutation burden.

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