KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance Journal Article


Authors: Zavitsanou, A. M.; Pillai, R.; Hao, Y.; Wu, W. L.; Bartnicki, E.; Karakousi, T.; Rajalingam, S.; Herrera, A.; Karatza, A.; Rashidfarrokhi, A.; Solis, S.; Ciampricotti, M.; Yeaton, A. H.; Ivanova, E.; Wohlhieter, C. A.; Buus, T. B.; Hayashi, M.; Karadal-Ferrena, B.; Pass, H. I.; Poirier, J. T.; Rudin, C. M.; Wong, K. K.; Moreira, A. L.; Khanna, K. M.; Tsirigos, A.; Papagiannakopoulos, T.; Koralov, S. B.
Article Title: KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance
Abstract: Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers. © 2023 The Author(s)
Keywords: adenocarcinoma; lung cancer; immunotherapy; nsclc; immune surveillance; t cell; nrf2; keap1; cp: cancer; cp: immunology; cd103 dc; luad
Journal Title: Cell Reports
Volume: 42
Issue: 11
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2023-11-28
Start Page: 113295
Language: English
DOI: 10.1016/j.celrep.2023.113295
PROVIDER: scopus
PUBMED: 37889752
PMCID: PMC10755970
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Charles Rudin
    489 Rudin