biostudies-literatureZhu MNCI NIH HHS1731-1748.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC10693909biostudies-literatureUnknown41(10)The role of tumor mutational burden (TMB) in shaping tumor immunity is a key question that has not been addressable using genetically engineered mouse models (GEMMs) of lung cancer. To induce TMB in lung GEMMs, we expressed an ultra-mutator variant of DNA polymerase-E (POLE)^P286R in lung epithelial cells. Introduction of Pole^P286R allele into Kras^G12D and Kras^G12D; p53^L/L (KP) models significantly increase their TMB. Immunogenicity and sensitivity to immune checkpoint blockade (ICB) induced by Pole is partially dependent on p53. Corroborating these observations, survival of NSCLC patients whose tumors have TP53^truncating mutations is shorter than those with TP53^WT with immunotherapy. Immune resistance is in part tCancer cellLoss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.PMC10693909R01 CA265884P50 CA070907R01 CA276058P30 CA142543R01 CA237405Xu LEglenen-Polat BCastrillon DHBender MEKowash RRDeng QGao JKim JAlessi JVMinna JDAwad MMZhu MRicciuti BCuevas IBennett ZTAkbay EAHuang HCfalseLoss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.The role of tumor mutational burden (TMB) in shaping tumor immunity is a key question that has not been addressable using genetically engineered mouse models (GEMMs) of lung cancer. To induce TMB in lung GEMMs, we expressed an ultra-mutator variant of DNA polymerase-E (POLE)^P286R in lung epithelial cells. Introduction of Pole^P286R allele into Kras^G12D and Kras^G12D; p53^L/L (KP) models significantly increase their TMB. Immunogenicity and sensitivity to immune checkpoint blockade (ICB) induced by Pole is partially dependent on p53. Corroborating these observations, survival of NSCLC patients whose tumors have TP53^truncating mutations is shorter than those with TP53^WT with immunotherapy. Immune resistance is in part t2023-01-01T00:00:00Z2023 Oct2025-04-04T08:18:20.864Z2025-04-04T08:18:20.864ZS-EPMC106939093777469810.1016/j.ccell.2023.09.006