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KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance [scRNA-seq]

ABSTRACT: Immune cells were isolated from the lungs of mice bearing KEAP1 mutant or wildtype tumors. We found that in KEAP1 mutant tumors there is a reduction in CD103 DCs and early activated T cells as well as an increase in exhausted CD8 T cells in comparison to WT controls.

ORGANISM(S): Mus musculus

PROVIDER: GSE241481 | GEO | 2023/11/27

REPOSITORIES: GEO

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KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance [RNA-seq]

Project description:Immune cells were isolated from the lungs of mice bearing KEAP1 mutant or wildtype tumors. We found that in KEAP1 mutant tumors there is a reduction in CD103 DCs and early activated T cells as well as an increase in exhausted CD8 T cells in comparison to WT controls.

2023-11-27 | GSE241480 | GEO

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

Project description: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.

| S-EPMC10755970 | biostudies-literature

Keap1 deficiency results in a genotype-specific dependency on Slc33a1

Project description:Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 (KEAP1), which lead to hyperactivation of the antioxidant program downstream from the nuclear factor, erythroid 2-like 2 (NRF2) transcription factor and correlates with poor prognosis1–3. We previously showed that Keap1 mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis4. To extend the investigation of genetic dependencies in the context of Keap1 mutation, we performed a druggable genome CRISPR-Cas9 screen in Keap1-mutant cells. This analysis uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), an endomembrane-associated protein with roles in autophagy regulation5, as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human Keap1-mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, validate Slc33a1 as a robust Keap1-mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to Slc33a1 dependency. Overall, our study provides a strong rationale for stratification of patients harboring KEAP1-mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with GEMMs to identify and validate genotype-specific therapeutic targets.

2020-04-13 | GSE145945 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-27 | GSE241482 | GEO

EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

Project description:Purpose: The goal of this study is to analyze the transcriptional pathways regulated by Emsy and Keap1 in subcutaneous mouse lung adenocarcinoma tumors. Methods: Keap1 wild type (KP) or mutant (KPK) cells expressing inducible shEmsy or shCTRL were implanted subcutaneously into the flanks of 6- to 8-week-old female syngeneic mice. Once tumors were measurable mice were treated with doxycycline to induce the shRNA expression. Knock down efficiency has been evaluated by western blot (using specific antibody for Emsy) and qPCR (using specific oligos for Emsy). Results: The transcriptomic analysis helps us to support our finding that Keap1-null tumors are characterized by suppression of the IFN response resulting from the stabilization of Emsy.

2021-01-15 | GSE164872 | GEO

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer

Project description:Keap1 mutant lung tumors were injected into mice and once lung tumors formed the mice were treated with anti-PD1, DRP-104, or the combination of the drugs. Immune cells and tumor cells were isolated from the lungs and ExCITE-seq was performed.

2024-04-03 | GSE237592 | GEO

EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

Project description:Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are characterized by worse overall outcomes and resistance to immunotherapy. Here, we identified a molecular mechanism by which KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY producing a BRCAness phenotype characterized by HRR defects and sensitivity to PARP inhibitors (PARPis). Defective HRR increases genomic instability leading to high tumor mutational burden (TMB), which prompts an innate immune response. Notably, EMSY accumulation also suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling, impairing the growth of KEAP1-mutant tumors. Our results suggest that targeting the PARP and STING pathways, individually or in combination, represent a novel therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

2022-01-04 | GSE178503 | GEO

Keap1 deletion-based Nrf2 activation accelerates mutant K-ras/p53-driven cholangiocarcinoma

Project description:Addition of liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, with hallmarks of Nrf2 activation.

2021-09-27 | GSE138101 | GEO

Keap1-dependent gene expression determined in the liver using conditional Keap1 knockout mice vs. genetic control mice

Project description:To compare hepatic gene expression in conditional Keap1 knockout (Alb-Cre:Keap1(flox/-)) and genetic control mice. Disruption of Keap1-mediated repression of Nrf2 signaling was expected to result in increased expression of Nrf2-regulated genes. Keywords: comparative expression profiling

2008-05-01 | GSE11287 | GEO

Single-cell RNA-seq of the esophagus of Keratin5CreERT2::Keap1 floxB/floxB and Keap1 floxB/floxB mice

Project description:We analyzed the esophagus of Keap1 conditional knockout mice. In these mice, there were both Keap1-normal and Keap1-deleted cells in the esophageal epithelium. To compare the gene expression of these cells, we conducted single-cell RNA-seq for the mice esophagus.

2023-02-19 | GSE197558 | GEO

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