2. Academic Validation
  3. Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden

Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden

  • Cancer Cell. 2023 Sep 26:S1535-6108(23)00322-7. doi: 10.1016/j.ccell.2023.09.006.
Mingrui Zhu 1,  Jiwoong Kim 2,  Qing Deng 1,  Biagio Ricciuti 3,  Joao V Alessi 3,  Buse Eglenen-Polat 1,  Matthew E Bender 1,  Hai-Cheng Huang 1,  Ryan R Kowash 1,  Ileana Cuevas 1,  Zachary T Bennett 4,  Jinming Gao 5,  John D Minna 6,  Diego H Castrillon 1,  Mark M Awad 3,  Lin Xu 7,  Esra A Akbay 8
Affiliations

Affiliations

  • 1 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.
  • 2 Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5 Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7 Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 8 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. Electronic address: [email protected].
PMID: 37774698 DOI: 10.1016/j.ccell.2023.09.006
Abstract

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 PoleP286R allele into KrasG12D and KrasG12D; p53L/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 TP53truncating mutations is shorter than those with TP53WT with immunotherapy. Immune resistance is in part through reduced antigen presentation and in part due to mutational heterogeneity. Total STING protein levels are elevated in Pole mutated KP tumors creating a vulnerability. A stable polyvalent STING agonist or p53 induction increases sensitivity to immunotherapy offering therapeutic options in these polyclonal tumors.

Keywords

GEMM; Immunotherapy; Kras; TMB; TP53; antigen presentation; clonality; heterogeneity; mice; patient survival.

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