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KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance [RNA-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: GSE241480 | GEO | 2023/11/27

REPOSITORIES: GEO

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KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance [scRNA-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 | GSE241481 | GEO

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

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

| PRJNA1008251 | ENA

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

Redox sensor KEAP1 promotes stemness and prevents reductive stress in exhausted CD8+ T cells via inhibiting NRF2

Project description:Persistent antigen stimulation exposes CD8+ T cells to various metabolic stresses and induces a dysfunctional state termed T-cell exhaustion. Exhausted CD8+ T cells are continuously replenished by a recently discovered self-renewing stem-like CD8+ T-cell subset, which maintains long-term immunity and provides proliferative burst in response to immunotherapies. Although the redox system plays an important role in regulating T-cell activation, how cellular redox affects the differentiation of stem-like and exhausted CD8+ T cells is incompletely understood. Here, we showed that both antigen stimulation and terminal differentiation reduced mitochondrial oxidation and reactive oxygen species (ROS) in exhausted CD8+ T cells, which displayed a chromatin state primed for regulation by the redox sensing KEAP1-NRF2 pathway. During chronic viral infection, KEAP1 promoted expansion of antiviral CD8+ T cells and facilitated their differentiation into the stem-like subset in a cell autonomous manner. In addition, KEAP1 was required for establishing proper transcriptional programs of stem-like and exhausted CD8+ T cells. Mechanistically, KEAP1 maintained oxidation by upregulating genes involved in mitochondrial oxidation and repressing NRF2-driven transcription of antioxidant pathways. Deleting KEAP1 binding domain in NRF2 released NRF2 from regulation by KEAP1, impaired expansion and stemness of CD8+ T cells, and dysregulated multiple metabolic pathways including redox pathways. Thus, our study revealed a novel role of the redox pathway in regulating the molecular program and differentiation of stem-like and exhausted CD8+ T cells during chronic antigen stimulation.

2024-11-11 | GSE224756 | GEO

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

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

| PRJNA1008265 | ENA

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

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

| PRJNA1008255 | ENA

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

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