KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Cell reports - 42(2023), 11 vom: 28. Nov., Seite 113295 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zavitsanou, Anastasia-Maria [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.12.2023 Date Revised 21.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2023.113295 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363818170 |
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| 100 | 1 | |a Zavitsanou, Anastasia-Maria |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance |
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| 500 | |a Date Revised 21.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CD103 DC | |
| 650 | 4 | |a CP: Cancer | |
| 650 | 4 | |a CP: Immunology | |
| 650 | 4 | |a KEAP1 | |
| 650 | 4 | |a LUAD | |
| 650 | 4 | |a NRF2 | |
| 650 | 4 | |a NSCLC | |
| 650 | 4 | |a T cell | |
| 650 | 4 | |a adenocarcinoma | |
| 650 | 4 | |a immune surveillance | |
| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a lung cancer | |
| 650 | 7 | |a Kelch-Like ECH-Associated Protein 1 |2 NLM | |
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| 700 | 1 | |a Pillai, Ray |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Warren L |e verfasserin |4 aut | |
| 700 | 1 | |a Bartnicki, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Karakousi, Triantafyllia |e verfasserin |4 aut | |
| 700 | 1 | |a Rajalingam, Sahith |e verfasserin |4 aut | |
| 700 | 1 | |a Herrera, Alberto |e verfasserin |4 aut | |
| 700 | 1 | |a Karatza, Angeliki |e verfasserin |4 aut | |
| 700 | 1 | |a Rashidfarrokhi, Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Solis, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Ciampricotti, Metamia |e verfasserin |4 aut | |
| 700 | 1 | |a Yeaton, Anna H |e verfasserin |4 aut | |
| 700 | 1 | |a Ivanova, Ellie |e verfasserin |4 aut | |
| 700 | 1 | |a Wohlhieter, Corrin A |e verfasserin |4 aut | |
| 700 | 1 | |a Buus, Terkild B |e verfasserin |4 aut | |
| 700 | 1 | |a Hayashi, Makiko |e verfasserin |4 aut | |
| 700 | 1 | |a Karadal-Ferrena, Burcu |e verfasserin |4 aut | |
| 700 | 1 | |a Pass, Harvey I |e verfasserin |4 aut | |
| 700 | 1 | |a Poirier, John T |e verfasserin |4 aut | |
| 700 | 1 | |a Rudin, Charles M |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Kwok-Kin |e verfasserin |4 aut | |
| 700 | 1 | |a Moreira, Andre L |e verfasserin |4 aut | |
| 700 | 1 | |a Khanna, Kamal M |e verfasserin |4 aut | |
| 700 | 1 | |a Tsirigos, Aristotelis |e verfasserin |4 aut | |
| 700 | 1 | |a Papagiannakopoulos, Thales |e verfasserin |4 aut | |
| 700 | 1 | |a Koralov, Sergei B |e verfasserin |4 aut | |
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