Search

The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) carries a high mortality, and efficacious therapy is lacking. Therapy using chimeric antigen receptor (CAR) T cells has been used efficaciously against hematologic malignancies, but the curative effect against solid tumors is not satisfactory. A lack of antigen targets is one of the main reasons for this limited efficacy. Previously, we showed that lung-specific X (LUNX; also known as BPIFA1, PLUNC, and SPLUNC1) is overexpressed in lung cancer cells. Here, we constructed a CAR-T-cell-based strategy to target LunX (CARLunX T cells). CAR T cells were developed so that, upon specific recognition of LunX, they secreted cytokines and killed LunX-positive NSCLC cells. In vitro, CARLunX T cells displayed enhanced toxicity toward NSCLC lines and production of cytokines and showed specific LunX-dependent recognition of NSCLC cells. Adoptive transfer of CARLunX T cells induced regression of established metastatic lung cancer xenografts and prolonged survival. CARLunX T cells could infiltrate into the tumor. Also, we constructed a patient-derived xenograft model of lung cancer. After therapy with CARLunX T cells, tumor growth was suppressed, and survival was prolonged significantly. Together, our findings offer preclinical evidence of the immunotherapeutic targeting of LunX as a strategy to treat NSCLC.

The epithelial sodium channel (ENaC) is responsible for Na+ and fluid absorption across colon, kidney, and airway epithelia. We have previously identified SPLUNC1 as an autocrine inhibitor of ENaC. We have now located the ENaC inhibitory domain of SPLUNC1 to SPLUNC1's N terminus, and a peptide corresponding to this domain, G22-A39, inhibited ENaC activity to a similar degree as full-length SPLUNC1 (~2.5 fold). However, G22-A39 had no effect on the structurally related acid-sensing ion channels, indicating specificity for ENaC. G22-A39 preferentially bound to the β-ENaC subunit in a glycosylation-dependent manner. ENaC hyperactivity is contributory to cystic fibrosis (CF) lung disease. Addition of G22-A39 to CF human bronchial epithelial cultures (HBECs) resulted in an increase in airway surface liquid height from 4.2 ± 0.6 to 7.9 ± 0.6 |mm, comparable to heights seen in normal HBECs, even in the presence of neutrophil elastase. Our data also indicate that the ENaC inhibitory domain of SPLUNC1 may be cleaved away from the main molecule by neutrophil elastase, which suggests that it may still be active during inflammation or neutrophilia. Furthermore, the robust inhibition of ENaC by the G22-A39 peptide suggests that this peptide may be suitable for treating CF lung disease. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) carries a high mortality, and efficacious therapy is lacking. Therapy using chimeric antigen receptor (CAR) T cells has been used efficaciously against hematologic malignancies, but the curative effect against solid tumors is not satisfactory. A lack of antigen targets is one of the main reasons for this limited efficacy. Previously, we showed that lung-specific X (LUNX; also known as BPIFA1, PLUNC, and SPLUNC1) is overexpressed in lung cancer cells. Here, we constructed a CAR-T-cell-based strategy to target LunX (CAR LunX T cells). CAR T cells were developed so that, upon specific recognition of LunX, they secreted cytokines and killed LunX-positive NSCLC cells. In vitro , CAR LunX T cells displayed enhanced toxicity toward NSCLC lines and production of cytokines and showed specific LunX-dependent recognition of NSCLC cells. Adoptive transfer of CAR LunX T cells induced regression of established metastatic lung cancer xenografts and prolonged survival. CAR LunX T cells could infiltrate into the tumor. Also, we constructed a patient-derived xenograft model of lung cancer. After therapy with CAR LunX T cells, tumor growth was suppressed, and survival was prolonged significantly. Together, our findings offer preclinical evidence of the immunotherapeutic targeting of LunX as a strategy to treat NSCLC., (© 2020 The Author(s).)

Introduction: Lung cancer is the most common cause of cancer-related death among males and females. The diagnosis of lung cancer is of great importance for clinical considerations and follow-up treatment. This study aimed to examine the expression of CEA, LUNX, and CK19 biomarkers in the cancerous and healthy tissues of patients suffering from NSCLC. Methods: In this study, 30 patients with NSCLCs referring to Masih Daneshvari Hospital in Tehran were voluntarily selected prior to taking any treatment. A tissue sample from the center and a sample of healthy tissues close to the cancerous masses were prepared by a specialist in the bronchoscopy sector and tested using real-time RT-PCR. Results: Positive CEA mRNA was observed in cancerous tissues in the center of tumors of 25 out of 30 cases. In the healthy tissue group, the same was found in 10 out of 30 cases (P<0.001). The markers CK19 and LUNX mRNAs showed to be positive in cancerous samples in the center of tumors of 15 and 22 out of 30 cases, and in the healthy tissue group, the expression was observed in 5 and 4 out of 30 cases, respectively(P<0.001). Conclusion: This study confirms that the aformentioed markers are the ones with a relatively appropriate sensitivity and specificity for the diagnosis of lung cancer.

Background: Anthracosis of the lung occurs due to the deposition of carbon and silica in the mucosa and submucosa, manifested as black lesions. The association of anthracosis with lung cancer has remained to be clearly elucidated The current study aimed to assess the P16, CDH1 and LUNX genes expression level to evaluate the association of anthracotic lesions in the lungs with the occurrence of non-small cell lung cancer. Methods: Forty biopsy samples were taken from the center and 40 from the margins of black anthracotic lesions in the lungs; RNA was extracted from the samples and cDNA was synthesized. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed to assess the expression of P16, CDH1 and LUNX genes. All steps were performed in triplicate. Results: A significant reduction in P16 gene expression was noted at the center compared to the margins of the lesions (P<0.001). expression level of CDH1 at the center of lesions was significantly lower than margins (P<0.001). However, LUNX gene had significantly higher expressionlevel at the center compared to margins (P<0.001). Conclusion: Decreased expression of P16 and CDH1 and increased expression of LUNX tumor genes were noted at the center of anthracotic lesions. Significant increase in expression of LUNX gene in NSCLC indicates an association between anthracosis and NSCLC, according to which, anthracotic patients may carry a high risk for NSCLC., (Creative Commons Attribution License)

The identification of novel therapeutic targets in lung cancer is an urgent challenge. We found lung-specific X protein (LunX) is overexpressed in lung cancer and promotes primary tumor growth and metastatic colonization. The antibody against LunX appears to be potentially applicable for therapeutic use in the future, given its efficacy in preclinical models. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cancer worldwide. However, no specific biomarker has been found in diagnosis and evaluation of therapeutic efficacy for lung cancer. The human lung-specific X protein gene (LUNX) was recently identified with a feature of lung tissue specificity. We applied the fluorescent quantitative polymerase chain reaction method to examine LUNX mRNA in plasma and peripheral blood mononuclear cells (PBMC) in patients with non-small cell lung cancer (NSCLC), benign lung diseases, extrapulmonary tumors, and healthy subjects. The results showed that LUNX mRNA in both of plasma and PBMC were significantly higher in lung cancer patients compared to other groups. In plasma, there were higher sensitivity and negative predictive value of LUNX mRNA than in PBMC. Patients with III~IV stages of lung cancer had more LUNX mRNA in plasma than the early stage of lung cancer sufferers. After a period of therapy, significant reductions of plasma LUNX mRNA in patients with I and II stages of lung cancer were found. Levels of plasma LUNX mRNA in patients who had succeeded to respond to therapy decreased compared to prior treatment. On the other hand, the post-treatment level was obviously increased in patients that had failed to respond to therapy. Patients with negative plasma LUNX mRNA after therapy displayed a favorable prognosis and survival rate. These preliminary data suggested that cell-free LUNX mRNA in plasma as a non-invasive biomarker, is superior to peripheral intracellular LUNX mRNA, and plays a critical role in specific diagnosis and prognostic prediction of non-small cell lung cancer.

Detection of micrometastases plays an important role in early-stage and recurrent cancer diagnosis. In the study, a new method of screening micrometastases of lung cancer in peripheral blood by magnetic nanoparticles (MNPs) and quantum dots (QDs) was developed to achieve early diagnosis and recurrence prevention. MNPs were prepared by combining miniemulsion polymerization and Stöber coating methods. QDs were prepared by using Cd(Ac)(2) · 2H(2)O and oxygen-free NaHTe with thioglycolic acid as the stabilizer. The carbodiimide-mediated condensation method was used to couple pan-cytokeratin (pan-ck) antibody (Ab) to the surface of the MNPs, and Lunx and SP-A Abs to the surface of the QDs. After four kinds of epithelial tumor cells were enriched by MNPs coupled with pan-ck Ab (MNP-pan-ck), lung cancer cells A549 and SPC-A-1 were successfully identified by QDs with double-labeled Abs. Finally, 32 patients with non-small cell lung cancer (NSCLC) were collected, out of 26 cases with the enriched circulating tumor cells (CTCs), 21 cases were successfully identified by QDs. Therefore, a new method was established in which MNP-pan-ck collected CTCs and QDs with double-labeled Abs could be used simultaneously to identify CTCs from NSCLC patients.