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Identification of Key Genes Driving Tumor Associated Macrophage Migration and Polarization Based on Immune Fingerprints of Lung Adenocarcinoma.

ABSTRACT: The identification of reliable indicators in the tumor microenvironment (TME) is critical for tumor prognosis. Tumor associated macrophages (TAMs) are the major component of non-tumor stromal cells in TME and have increasingly been recognized as a predictive biomarker for lung adenocarcinoma (LUAD) prognosis. Here, we report the development of a prognosis model for LUAD using three immune-related genes (IRGs) detected in The Cancer Genome Atlas (TCGA) which potentially regulate TAMs in TME. In 497 LUAD patients, higher immune scores conferred better overall survival (OS). We identified 93 hub IRGs out of 234 for further prognostic significance. Among them, three IRGs (BTK, Cd1c, and S100P) were proved to be closely correlated to the prognosis of patients with LUAD. Moreover, the immune risk score (IRS) based on the gene expression level of the three IRGs was an independent prognostic factor for OS. Higher IRS predicted lower OS, higher mortality and worse tumor stage. With a good predictive ability [area under the ROC curve (AUC) in TCGA = 0.701, AUC in GEO = 0.722], the IRS contributed to a good risk stratification ability of the nomogram. Immunologically, the three IRGs were related to M1 macrophages and NK cell subsets in TME. Interestingly, by characterizing these immune components in situ we found that S100P is a driver for tumor cells to induce TAM migration and M2 polarization in the immunosuppressive tumor niche. We identified the key genes driving TAM migration and transformation and elucidated the immune landscape of LUAD. The data suggest that IRGs from TME have the potential to become indicators for estimating cancer prognosis and guiding individualized treatment.

SUBMITTER: Wu J

PROVIDER: S-EPMC8600368 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLong non-coding RNAs (lncRNAs) are critical regulators in lung adenocarcinoma (LUAD). M2-type tumor-associated macrophages (TAMs) also play oncogenic roles in LUAD. However, the involvement of lncRNAs in TAM activation is still largely unknown.MethodsThe expressions of LARRPM, LINC00240 and CSF1 were determined by RT-qPCR. The regulation of LINC00240 and CSF1 by LARRPM was investigated by RNA-protein pull-down, RNA immunoprecipitation, chromatin immunoprecipitation and bisulfite DNA sequencing. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of LARRPM.ResultsThe lncRNA LARRPM was expressed at low levels in LUAD tissues and cells. The low expression of LARRPM was correlated with advanced stage and poor survival of patients with LUAD. Functional experiments revealed that LARRPM suppressed LUAD cell proliferation, migration and invasion, and promoted apoptosis. LARRPM also repressed macrophage M2 polarization and infiltration. Taken together, LARRPM significantly restricted LUAD progression in vivo. Mechanistically, LARRPM bound and recruited DNA demethylase TET1 to the promoter of its anti-sense strand gene LINC00240, leading to a decrease in DNA methylation level of the LINC00240 promoter and transcriptional activation of LINC00240. Functional rescue assays suggested that the lncRNA LINC00240 was responsible for the roles of LARRPM in the malignant behavior of LUAD cells. LARRPM decreased the binding of TET1 to the CSF1 promoter, resulting in increased DNA methylation of the CSF1 promoter and transcriptional repression of CSF1, which is responsible for the roles of LARRPM in macrophage M2 polarization and infiltration. The TAMs educated by LUAD cells exerted oncogenic roles, which was negatively regulated by LARRPM expressed in LUAD cells.ConclusionsLARRPM restricts LUAD progression through repressing both LUAD cell and macrophages. These data shed new insights into the regulation of LUAD progression by lncRNAs and provide data on the potential utility of LARRPM as a target for LUAD treatment.

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Identification of Key Genes Driving Tumor Associated Macrophage Migration and Polarization Based on Immune Fingerprints of Lung Adenocarcinoma.

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