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Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, only few patients respond to this promising approach that has the potential to cure even metastatic disease. We hypothesize that the success of the treatment is impaired by the presence of immunosuppressors in the tumor microenvironment and therefore investigated the role of the immunosuppressive glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. Binding assays with different leucocyte cell lines and subsequent transcriptome analyses reveal that glycodelin indeed interacts with immune cellsin vitroand regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. Furthermore, multiplex immunofluorescence staining of glycodelin and different leucocytes in tumor microarray samples of patients with NSCLC show that glycodelin binds to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. Interestingly, we observe that high serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. Our findings demonstrate that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer.

To explore the relationship between cancer cell SREBF1 expression, lipid droplets (LDs) formation, and the sensitivity to chemotherapies, we cultured lung adenocarcinoma cells H1299 (with LD) and H1563 (without LD) in a serum-free basal medium (BM) or neutrophil degranulation products containing medium (NDM), and tested cell responses to cisplatin and etoposide. By using the DESeq2 Bioconductor package, we detected 674 differentially expressed genes (DEGs) associated with NDM/BM differences between two cell lines, many of these genes were associated with the regulation of sterol and cholesterol biosynthesis processes. Specifically

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (

Genes 13(5), 759 (2022). doi:10.3390/genes13050759, Published by MDPI, Basel

Transmembrane serine protease 2 (TMPRSS2) has been intensively investigated during the current Sars‑CoV‑2 pandemic as a virus activating protease. Furthermore

Simple Summary Lung cancer is one of the most commonly diagnosed cancers worldwide and the most common cause of cancer-related deaths. During lung carcinogenesis, epigenetic alteration of tumor-related genes is a frequent event and especially silencing of tumor suppressor genes is often found. In our work, we identified Iroquois homeobox 1 (IRX1) from the lung cancer susceptibility locus 5p15.33, as an epigenetically silenced target gene. We report frequent epigenetic inactivation of IRX1 in primary lung adenocarcinoma. Moreover, reduced expression and hypermethylation of IRX1 was correlated with an impaired prognosis of patients with lung adenocarcinoma. Functionally, IRX1 overexpression induced signs of apoptosis including fragmented nuclei and expression of a proapoptotic regulator. Loss of IRX1 expression by its promoter hypermethylation can serve as a diagnostic and prognostic lung cancer biomarker. Abstract Iroquois homeobox (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the IRX1 gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the IRX1 promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant IRX1 methylation was significantly correlated with reduced IRX1 expression. In normal lung samples, the IRX1 promoter showed lower median DNA methylation levels (

Iroquois homeobox (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the IRX1 gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the IRX1 promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant IRX1 methylation was significantly correlated with reduced IRX1 expression. In normal lung samples, the IRX1 promoter showed lower median DNA methylation levels (&lt, 10%) compared to primary adenocarcinoma (ADC, 22%) and squamous cell carcinoma (SQCC, 14%). A significant hypermethylation and downregulation of IRX1 was detected in ADC and SQCC compared to matching normal lung samples (p &lt, 0.0001). Low IRX1 expression was significantly correlated with impaired prognosis of ADC patients (p = 0.001). Reduced survival probability was also associated with higher IRX1 promoter methylation (p = 0.02). Inhibition of DNA methyltransferase (DNMT) activity reactivated IRX1 expression in human lung cancer cell lines. Induced DNMT3A and EZH2 expression was correlated with downregulation of IRX1. On the cellular level, IRX1 exhibits nuclear localization and expression of IRX1 induced fragmented nuclei in cancer cells. Localization of IRX1 and induction of aberrant nuclei were dependent on the presence of the homeobox of IRX1. By data mining, we showed that IRX1 is negatively correlated with oncogenic pathways and IRX1 expression induces the proapoptotic regulator BAX. In conclusion, we report that IRX1 expression is significantly associated with improved survival probability of ADC patients. IRX1 hypermethylation may serve as molecular biomarker for ADC diagnosis and prognosis. Our data suggest that IRX1 acts as an epigenetically regulated tumor suppressor in the pathogenesis of lung cancer.