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

Mingrui Zhu; Jiwoong Kim; Qing Deng; Biagio Ricciuti; Joao V Alessi; Buse Eglenen-Polat; Matthew E Bender; Hai-Cheng Huang; Ryan R Kowash; Ileana Cuevas; Zachary T Bennett; Jinming Gao; John D Minna; Diego H Castrillon; Mark M Awad; Lin Xu; Esra A Akbay

doi:10.1016/j.ccell.2023.09.006

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

Cancer Cell. 2023 Oct 9;41(10):1731-1748.e8. doi: 10.1016/j.ccell.2023.09.006. Epub 2023 Sep 28.

Authors

Mingrui Zhu¹, Jiwoong Kim², Qing Deng¹, Biagio Ricciuti³, Joao V Alessi³, Buse Eglenen-Polat¹, Matthew E Bender¹, Hai-Cheng Huang¹, Ryan R Kowash¹, Ileana Cuevas¹, Zachary T Bennett⁴, Jinming Gao⁵, John D Minna⁶, Diego H Castrillon¹, Mark M Awad³, Lin Xu⁷, Esra A Akbay⁸

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].

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 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 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / therapy
Humans
Lung Neoplasms* / drug therapy
Mice
Mutation
Proto-Oncogene Proteins p21(ras) / genetics
Tumor Suppressor Protein p53 / genetics

Substances

Proto-Oncogene Proteins p21(ras)
Tumor Suppressor Protein p53

Abstract

Publication types

MeSH terms

Substances

Grants and funding