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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE241482 | GEO | 2023/11/27

REPOSITORIES: GEO

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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 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 [RNA-seq]

2023-11-27 | GSE241480 | 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 [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

Lung adenocarcinoma patients with KEAP1 mutation harboring low immune cell infiltration and low activity of immune environment.

Project description:BackgroundKelch-like ECH-associated protein 1 (KEAP1) has been identified as a cancer driver gene in lung adenocarcinoma (LUAD), and increased evidence has given us clues about the association of KEAP1 mutation and immune characteristics. We assessed the association between KEAP1 mutation and tumor microenvironment in LUAD systematically.MethodsWith the data collected from The Cancer Genome Atlas (TCGA), we evaluated the association of KEAP1 mutation with tumor infiltrating leukocytes (TILs), including dendritic cell, CD8 T cell, CD4 T cell, neutrophil, B cells, and macrophage. Expression differences of the markers of those immune cells were also measured. We further compared the expression of antigen presentation genes and chemokines and the enrichment score of immune-related pathways.ResultsKEAP1 mutation had significant association with lower TILs and cytotoxic T lymphocyte. Strikingly, almost all of antigen presentation genes and chemokine showed lower expression in KEAP1-mutated tumors. Moreover, most of immune-related pathways were less active in KEAP1-mutated tumors. As expected, KEAP1-wild type LUADs favored better overall survival after immunotherapy. Finally, one patient harboring KEAP1 mutation along with a lack of immune cells infiltration in tumor microenvironment failed to respond to checkpoint inhibitor despite high tumor mutational burden (TMB).ConclusionsKEAP1 mutation has a significant effect on the tumor immune milieu of LUAD and may play as a predictive biomarker of immunotherapy for LUAD patients.

| S-EPMC8447911 | biostudies-literature

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade

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

2023-02-24 | GSE218431 | GEO

Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated and characterized C57Bl/6-derived KPC (KRasG12D, TRP53R172H ) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies, tumor growth and metastatic potential were significantly diminished by depletion of TF or Par-1 in cancer cells or by genetic or pharmacologic reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1-deleted KPC cells (KPC-Par-1KO) failed to generate sizable tumors, a phenotype completely rescued by restoration of Par-1 expression. Expression profiling of KPC and KPC-Par-1KO cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly, KPC-Par-1KO cells failed to form tumors in immune-competent mice but displayed robust tumor growth comparable to that observed with control KPC cells in immune-compromised NSG mice. Immune cell depletion studies indicated that CD8 T cells, but not CD4 cells or natural killer cells, mediated elimination of KPC-Par-1KO tumor cells in C57Bl/6 mice. These results demonstrate that PDAC is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor cell-derived PAR-1 and further indicate that one key mechanism of thrombin/PAR-1-mediated tumor growth is suppression of antitumor immunity in the tumor microenvironment. SIGNIFICANCE: The tissue factor-thrombin-PAR-1 signaling axis in tumor cells promotes PDAC growth and disease progression with one key mechanism being suppression of antitumor immunity in the microenvironment.

| S-EPMC6699516 | biostudies-literature

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade.

Project description:Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.

| S-EPMC9981575 | biostudies-literature

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