Dataset Information

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

ABSTRACT:

Background

Kelch-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.

Methods

With 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.

Results

KEAP1 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).

Conclusions

KEAP1 mutation has a significant effect on the tumor immune milieu of LUAD and may play as a predictive biomarker of immunotherapy for LUAD patients.

SUBMITTER: Cheng W

PROVIDER: S-EPMC8447911 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increasing studies have proved that malignant tumors are associated with energy metabolism. This study was aimed to explore biological variables that impact the prognosis of patients in the glycolysis-related subgroups of lung adenocarcinoma (LUAD). The mRNA expression profiling and mutation data in large LUAD samples were collected from the Cancer Genome Atlas (TCGA) database. Then, we identified the expression level and prognostic value of glycolysis-related genes, as well as the fractions of 22 immune cells in the tumor microenvironment. The differences between glycolysis activity, mutation, and immune infiltrates were discussed in these groups, respectively. Two hundred fifty-five glycolysis-related genes were identified from gene set enrichment analysis (GSEA), of which 43 genes had prognostic values (p < 0.05). Next, we constructed a glycolysis-related competing endogenous RNA (ceRNA) network which related to the survival of LUAD. Then, two subgroups of LUAD (clusters 1 and 2) were identified by applying unsupervised consensus clustering to 43 glycolysis-related genes. The survival analysis showed that the cluster 1 patients had a worse prognosis (p < 0.001), and upregulated differentially expressed genes (DEGs) are interestingly enriched in malignancy-related biological processes. The differences between the two subgroups are SPTA1, KEAP1, USH2A, and KRAS among top 10 mutated signatures, which may be the underlying mechanism of grouping. Combined high tumor mutational burden (TMB) with tumor subgroups preferably predicts the prognosis of LUAD patients. The CIBERSORT algorithm results revealed that low TMB samples were concerned with increased infiltration level of memory resting CD4+ T cell (p = 0.03), resting mast cells (p = 0.044), and neutrophils (p = 0.002) in cluster 1 and high TMB samples were concerned with increased infiltration level of memory B cells, plasma cells, CD4 memory-activated T cells, macrophages M1, and activated mast cells in cluster 2, while reduced infiltration of monocytes, resting dendritic cells, and resting mast cells was captured in cluster 2. In conclusion, significant different gene expression characteristics were pooled according to the two subgroups of LUAD. The combination of subgroups, TMB and tumor-infiltrating immune cell signature, might be a novel prognostic biomarker in LUAD.