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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.

SUBMITTER: Zavitsanou AM

PROVIDER: S-EPMC10755970 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Zavitsanou Anastasia-Maria AM Pillai Ray R Hao Yuan Y Wu Warren L WL Bartnicki Eric E Karakousi Triantafyllia T Rajalingam Sahith S Herrera Alberto A Karatza Angeliki A Rashidfarrokhi Ali A Solis Sabrina S Ciampricotti Metamia M Yeaton Anna H AH Ivanova Ellie E Wohlhieter Corrin A CA Buus Terkild B TB Hayashi Makiko M Karadal-Ferrena Burcu B Pass Harvey I HI Poirier John T JT Rudin Charles M CM Wong Kwok-Kin KK Moreira Andre L AL Khanna Kamal M KM Tsirigos Aristotelis A Papagiannakopoulos Thales T Koralov Sergei B SB

Cell reports 20231026 11

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 immu ...[more]

PMID: 37889752

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Project description:PurposeIt is still unclear whether KEAP1 mutation is detrimental to immunotherapy of lung adenocarcinoma (LUAD) patients, we try to analyse the exact changes in the TME in LUAD patients with KEAP1 mutations and to identify key factors influencing prognosis.Experimental designA total of 1,029 patients with lung squamous carcinoma (LUSC) or LUAD with data obtained from The Cancer Genome Atlas were included in this study. The TME and OS of patients with LUAD stratified by mutant versus wild-type KEAP1 status were comprehensively measured. Moreover, we classified LUAD patients with KEAP1 mutations into three subtypes, by unsupervised consensus clustering. We further analysed the TME, OS, commutated genes and metabolic pathways of different subgroups. A total of 40 LUAD patients underwent immunotherapy were collected and classified into mutant KEAP1 group and wild-type KEAP1 group. We also conducted immunohistochemical staining in KEAP1-MT groups.ResultSuppressed TME was observed not only in LUAD patients but also in LUSC patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than wild-type KEAP1. Unsupervised consensus clustering analysis suggested that the three subtypes of patients exhibited different densities of neutrophil infiltration and had different OS results: cluster 2 patients had significantly higher levels of neutrophils had significantly worse prognoses than those of patients in clusters 1 and 3 and patients with wild-type KEAP1. Univariate and multivariate Cox analyses proved that a high density of neutrophils was significantly associated with worse OS and immunohistochemical staining proved that shorter PFS showed high density of neutrophils.ConclusionKEAP1 mutation significantly suppresses the tumour immune microenvironment in LUAD patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than with wild-type KEAP1. Neutrophils may play an important role in the prognosis of LUAD patients with KEAP1 mutations and may provide a promising therapeutic target.

Dataset Information

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Publications

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

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