Zhu et al. expressed an ultra-mutator variant of DNA polymerase-E (POLE)P286R in lung epithelial cells of KrasG12D and KrasG12D; p53L/L (KP) models to generate lung GEMM with high TMB and accelerated progression. Loss of p53 in the PoleP86R-mutant (KPO) GEMM model reduced antigen presentation and increased tumor heterogeneity, creating immunosuppressive tumor microenvironments and resistance to ICB, which is consistent with shorter overall survival of NSCLC patients with TP53 truncating mutations receiving ICB. A STING agonist or ectopic p53 induction increased the MHC-I expression, T cell killing, and immunogenicity of KPO tumors.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (2) Quantitative Biomedical Res
Author Info: (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) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (4) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (5) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (7) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (8) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (9) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (10) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (11) Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (12) 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. (13) Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (14) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. (15) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (16) 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. (17) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA. Electronic address: esra.akbay@utsouthwestern.edu.
