KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance

Research output: Contribution to journal › Journal article › Research › peer-review

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KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. / Zavitsanou, Anastasia Maria; Pillai, Ray; Hao, Yuan; Wu, Warren L.; Bartnicki, Eric; Karakousi, Triantafyllia; Rajalingam, Sahith; Herrera, Alberto; Karatza, Angeliki; Rashidfarrokhi, Ali; Solis, Sabrina; Ciampricotti, Metamia; Yeaton, Anna H.; Ivanova, Ellie; Wohlhieter, Corrin A.; Buus, Terkild B.; Hayashi, Makiko; Karadal-Ferrena, Burcu; Pass, Harvey I.; Poirier, John T.; Rudin, Charles M.; Wong, Kwok Kin; Moreira, Andre L.; Khanna, Kamal M.; Tsirigos, Aristotelis; Papagiannakopoulos, Thales; Koralov, Sergei B.

In: Cell Reports, Vol. 42, No. 11, 113295, 28.11.2023, p. 1-25.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Zavitsanou, AM, Pillai, R, Hao, Y, Wu, WL, Bartnicki, E, Karakousi, T, Rajalingam, S, Herrera, A, Karatza, A, Rashidfarrokhi, A, Solis, S, Ciampricotti, M, Yeaton, AH, Ivanova, E, Wohlhieter, CA, Buus, TB, Hayashi, M, Karadal-Ferrena, B, Pass, HI, Poirier, JT, Rudin, CM, Wong, KK, Moreira, AL, Khanna, KM, Tsirigos, A, Papagiannakopoulos, T & Koralov, SB 2023, 'KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance', Cell Reports, vol. 42, no. 11, 113295, pp. 1-25. https://doi.org/10.1016/j.celrep.2023.113295

APA

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., ... Koralov, S. B. (2023). KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. Cell Reports, 42(11), 1-25. [113295]. https://doi.org/10.1016/j.celrep.2023.113295

Vancouver

Zavitsanou AM, Pillai R, Hao Y, Wu WL, Bartnicki E, Karakousi T et al. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. Cell Reports. 2023 Nov 28;42(11):1-25. 113295. https://doi.org/10.1016/j.celrep.2023.113295

Author

Zavitsanou, Anastasia Maria ; Pillai, Ray ; Hao, Yuan ; Wu, Warren L. ; Bartnicki, Eric ; Karakousi, Triantafyllia ; Rajalingam, Sahith ; Herrera, Alberto ; Karatza, Angeliki ; Rashidfarrokhi, Ali ; Solis, Sabrina ; Ciampricotti, Metamia ; Yeaton, Anna H. ; Ivanova, Ellie ; Wohlhieter, Corrin A. ; Buus, Terkild B. ; Hayashi, Makiko ; Karadal-Ferrena, Burcu ; Pass, Harvey I. ; Poirier, John T. ; Rudin, Charles M. ; Wong, Kwok Kin ; Moreira, Andre L. ; Khanna, Kamal M. ; Tsirigos, Aristotelis ; Papagiannakopoulos, Thales ; Koralov, Sergei B. / KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. In: Cell Reports. 2023 ; Vol. 42, No. 11. pp. 1-25.

Bibtex

@article{a9a19e6aa1424de585247194c64df735,
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.",
keywords = "adenocarcinoma, CD103 DC, CP: Cancer, CP: Immunology, immune surveillance, immunotherapy, KEAP1, LUAD, lung cancer, NRF2, NSCLC, T cell",
author = "Zavitsanou, {Anastasia Maria} and Ray Pillai and Yuan Hao and Wu, {Warren L.} and Eric Bartnicki and Triantafyllia Karakousi and Sahith Rajalingam and Alberto Herrera and Angeliki Karatza and Ali Rashidfarrokhi and Sabrina Solis and Metamia Ciampricotti and Yeaton, {Anna H.} and Ellie Ivanova and Wohlhieter, {Corrin A.} and Buus, {Terkild B.} and Makiko Hayashi and Burcu Karadal-Ferrena and Pass, {Harvey I.} and Poirier, {John T.} and Rudin, {Charles M.} and Wong, {Kwok Kin} and Moreira, {Andre L.} and Khanna, {Kamal M.} and Aristotelis Tsirigos and Thales Papagiannakopoulos and Koralov, {Sergei B.}",
note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = nov,
day = "28",
doi = "10.1016/j.celrep.2023.113295",
language = "English",
volume = "42",
pages = "1--25",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",

}

RIS

TY - JOUR

T1 - KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance

AU - Zavitsanou, Anastasia Maria

AU - Pillai, Ray

AU - Hao, Yuan

AU - Wu, Warren L.

AU - Bartnicki, Eric

AU - Karakousi, Triantafyllia

AU - Rajalingam, Sahith

AU - Herrera, Alberto

AU - Karatza, Angeliki

AU - Rashidfarrokhi, Ali

AU - Solis, Sabrina

AU - Ciampricotti, Metamia

AU - Yeaton, Anna H.

AU - Ivanova, Ellie

AU - Wohlhieter, Corrin A.

AU - Buus, Terkild B.

AU - Hayashi, Makiko

AU - Karadal-Ferrena, Burcu

AU - Pass, Harvey I.

AU - Poirier, John T.

AU - Rudin, Charles M.

AU - Wong, Kwok Kin

AU - Moreira, Andre L.

AU - Khanna, Kamal M.

AU - Tsirigos, Aristotelis

AU - Papagiannakopoulos, Thales

AU - Koralov, Sergei B.

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023/11/28

Y1 - 2023/11/28

N2 - 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.

AB - 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.

KW - adenocarcinoma

KW - CD103 DC

KW - CP: Cancer

KW - CP: Immunology

KW - immune surveillance

KW - immunotherapy

KW - KEAP1

KW - LUAD

KW - lung cancer

KW - NRF2

KW - NSCLC

KW - T cell

U2 - 10.1016/j.celrep.2023.113295

DO - 10.1016/j.celrep.2023.113295

M3 - Journal article

C2 - 37889752

AN - SCOPUS:85174808583

VL - 42

SP - 1

EP - 25

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

M1 - 113295

ER -

ID: 373833137