STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC

Li, Anlin; Wang, Yuanyuan; Yu, Zhixin; Tan, Zheng; He, Lina; Fu, Sha; Shi, Mengting; Du, Wei; Luo, Linfeng; Li, Zhichao; Liu, Jiaqing; Zhou, Yixin; Fang, Wenfeng; Yang, Yunpeng; Zhang, Li; Hong, Shaodong

doi:10.1016/j.jtho.2023.07.020

Cited by 10 publications

(1 citation statement)

References 55 publications

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“… 34 Recent two studies reported the utility of transcriptomic phenotypes to define KEAP1/NRF2-activated or STK11-deficient lung cancers, respectively. 35 , 36 It is interesting that the gene sets applying for identifying the transcriptomic phenotypes were similar between two studies. It suggests that mutations of different genes can caused similar functional downstream effects.…”

Section: Discussionmentioning

confidence: 97%

Redox ^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Wei,

Lu,

Zhang

et al. 2024

OncoImmunology

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Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redox high LUAD and redox low LUAD. Genetically, redox high LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redox high LUAD (72.5%) compared to redox low LUAD (17.4%), whereas EGFR mutations are more common in redox low LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redox high LUAD. The redox high phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redox high phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redox high phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

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Section: Discussionmentioning

confidence: 97%

Redox ^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Wei,

Lu,

Zhang

et al. 2024

OncoImmunology

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Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal Angiogenesis

Yan,

Wang,

Ouyang

et al. 2024

Asian Journal of Pharmaceutical Sciences

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miR-744-5p promotes T-cell differentiation via inhibiting STK11

Han,

Huang,

et al. 2024

Gene

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STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC

Cited by 10 publications

References 55 publications

Redox ^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Redox ^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal Angiogenesis

miR-744-5p promotes T-cell differentiation via inhibiting STK11

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STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC

Cited by 10 publications

References 55 publications

Redox high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Redox high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal Angiogenesis

miR-744-5p promotes T-cell differentiation via inhibiting STK11

Contact Info

Product

Resources

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Redox ^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

Redox ^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma