Abstract

Mutations in polymerases Pold1 and Pole exonuclease domains in humans are associated with increased cancer incidence, elevated tumor mutation burden (TMB) and response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond. Here we generated Pold1 and Pole proofreading mutator mice and show that ICB treatment of mice with high TMB tumors did not improve survival as only a subset of tumors responded. Similarly, introducing the mutator alleles into mice with Kras/p53 lung cancer did not improve survival, however, passaging mutator tumor cells in vitro without immune editing caused rejection in immune-competent hosts, demonstrating the efficiency by which cells with antigenic mutations are eliminated. Finally, ICB treatment of mutator mice earlier, before observable tumors delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the use of ICB in individuals at high risk for cancer prevention. HighlightsO_LIGermline somatic and conditional Pold1 and Pole exonuclease domain mutations in mice produce a mutator phenotype. C_LIO_LISpontaneous cancers arise in mutator mice that have genomic features comparable to human tumors with these mutations. C_LIO_LIICB treatment of mutator mice with tumors did not improve survival as only a subset of tumors respond. C_LIO_LIIntroduction of the mutator alleles into an autochthonous mouse lung cancer model also did not produce immunogenic tumors, whereas passaging mutator tumor cells in vitro caused immune rejection indicating efficient selection against antigenic mutations in vivo. C_LIO_LIProphylactic ICB treatment delayed cancer onset, improved survival, and selected for tumors with no aneuploidy. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/597960v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@6cd159org.highwire.dtl.DTLVardef@243fd1org.highwire.dtl.DTLVardef@1d9da6borg.highwire.dtl.DTLVardef@192be51_HPS_FORMAT_FIGEXP M_FIG C_FIG