학술논문
Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.
Document Type
Academic Journal
Author
Zhu M; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Kim J; Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Deng Q; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Ricciuti B; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Alessi JV; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Eglenen-Polat B; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Bender ME; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Huang HC; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Kowash RR; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Cuevas I; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Bennett ZT; Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Gao J; 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.; Minna JD; Simmons Comprehensive Cancer Center, Dallas, TX, USA; Department Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Castrillon DH; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, Dallas, TX, USA.; Awad MM; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Xu L; 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.; Akbay EA; 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.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101130617 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-3686 (Electronic) Linking ISSN: 15356108 NLM ISO Abbreviation: Cancer Cell Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: Declaration of interests J.G. has patents related to this work and is scientific co-founder and advisor of OncoNano Medicine, Inc. J.D.M. receives licensing fees from the NCI and UT Southwestern to distribute cell lines. J.V.A. receives Advisory Board fee from BMS. B.R. served as consultant/advisory board for Regeneron, AMGEN, and AstraZeneca and received honoraria from Targeted Oncology. M.M.A. reports serving as a consultant to Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, AbbVie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono; receiving research funding from Bristol-Myers Squibb, Eli Lilly, Genentech, and AstraZeneca.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests J.G. has patents related to this work and is scientific co-founder and advisor of OncoNano Medicine, Inc. J.D.M. receives licensing fees from the NCI and UT Southwestern to distribute cell lines. J.V.A. receives Advisory Board fee from BMS. B.R. served as consultant/advisory board for Regeneron, AMGEN, and AstraZeneca and received honoraria from Targeted Oncology. M.M.A. reports serving as a consultant to Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, AbbVie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono; receiving research funding from Bristol-Myers Squibb, Eli Lilly, Genentech, and AstraZeneca.
(Copyright © 2023 Elsevier Inc. All rights reserved.)