The combination of CD68 plus TAMs, CSF-1, and IL-6 is very likely to be a valuable independent predictor of survival in patients with NSCLC. Perhaps co-expression of CSF-1 and IL-6 induces interstitial TAMs to shift toward the tumor-promoting phenotype.

Background Long 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. Methods The 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. Results The 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. Conclusions LARRPM 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.

Background In the tumor microenvironment, programmed death ligand 1(PD-L1) is a key protein upregulated by tumor cells in immune escape. Tumor-associated macrophages (TAMs) play a major role in this immunosuppression. Osteopontin (OPN) is related to tumor metastasis and proliferation and immunosuppression. OPN is expressed not only by tumor cells, but also by TAMs. However, little is known of the relationship between OPN expressed by TAMs(TOPN) and PD-L1 in non-small cell lung cancer.MethodsTissue microarray was used to detect the expression of TOPN, TAMs and PD-L1 by multiple quantitative fluorescence staining in 509 NSCLC patients undergoing complete pulmonary resection. The correlations between TOPN, PD-L1 and clinicopathologic data were analyzed. And in vitro cell cocultures were further conducted to investigate the crosstalk between TOPN and Neoplastic PD-L1. The in vivo efficacy of TOPN was evaluated for PD-L1 expression in subcutaneous coculture mouse model of NSCLC.ResultsWe observed a positive association between the TOPN and PD-L1 expression in tumor tissues from 509 patients with NSCLC. In addition, survival analysis revealed that TOPN and PD-L1 were independent prognostic factors for overall survival(OS) and disease-free survival(DFS) of NSCLC patients. We further demonstrated that TOPN upregulated PD-L1 expression in NSCLC cells through NF-κB pathway in vitro. And the upregulation was inhibited by neutralization with anti-OPN antibody or NF-κB inhibitor after co-culture with macrophages. TOPN induced the PD-L1 expression in tumor-bearing mice, and promoted the tumor growth.ConclusionsTOPN/NF-κB axis plays a critical role in PD-L1 expression of NSCLC microenvironment. TOPN could be a potential therapeutic target for NSCLC.