International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

The mitochondrial protein YME1 Like 1 is important for non-small cell lung cancer cell growth.

The expression and biological function of the mitochondrial inner membrane protease YME1L (YME1 Like 1 ATPase) in NSCLC are tested here. Bioinformatical analyses and results from local human tissues show that YME1L expression is elevated in NSCLC tissues. YME1L upregulation was observed in primary and immortalized NSCLC cells. In NSCLC cells, shRNA-mediated silence of YME1L or dCas9/sgRNA-induced knockout (KO) of YME1L robustly suppressed cell growth and migration, and provoking apoptosis. YME1L shRNA/KO resulted in mitochondrial dysfunctions in NSCLC cells, leading to mitochondrial depolarization, ROS accumulation and ATP depletion. Conversely, ectopic YME1L overexpression augmented NSCLC cell proliferation and motility. Akt-S6K1 phosphorylation was reduced after YME1L shRNA/KO in primary NSCLC cells, but augmented after YME1L overexpression. Importantly, YME1L KO-caused anti-NSCLC cell activity was attenuated by a constitutively-activate Akt1 (S473D) construct. In vivo, subcutaneous NSCLC xenograft growth was remarkably slowed following intratumoral YME1L shRNA AAV injection in nude mice. YME1L knockdown, Akt-mTOR inactivation and ATP reduction were detected in YME1L-silenced NSCLC xenografts. Taken together, overexpressed YME1L in NSCLC exerts pro-tumorigenic function.

The sodium/myo-inositol co-transporter SLC5A3 promotes non-small cell lung cancer cell growth.

Identification of novel molecular signaling targets for non-small cell lung cancer (NSCLC) is important. The present study examined expression, functions and possible underlying mechanisms of the sodium/myo-inositol co-transporter SLC5A3 in NSCLC. The Cancer Genome Atlas (TCGA) database and local NSCLC tissue results demonstrated that SLC5A3 expression in NSCLC tissues (including patient-derived primary NSCLC cells) was significantly higher than that in normal lung tissues and lung epithelial cells. In primary NSCLC cells and immortalized lines, SLC5A3 depletion, using small hairpin RNA (shRNA) and CRSIRP/Cas9 methods, robustly impeded cell proliferation and migration, simultaneously provoking cell cycle arrest and apoptosis. Conversely, ectopic overexpression of SLC5A3 further enhanced proliferation and migration in primary NSCLC cells. The intracellular myo-inositol contents and Akt-mTOR activation were largely inhibited by SLC5A3 silencing or knockout (KO), but were augmented following SLC5A3 overexpression in primary NSCLC cells. Significantly, SLC5A3 KO-induced anti-NSCLC cell activity was largely ameliorated by exogenously adding myo-inositol or by a constitutively-active Akt construct. By employing the patient-derived xenograft (PDX) model, we found that the growth of subcutaneous NSCLC xenografts in nude mice was largely inhibited by intratumoral injection SLC5A3 shRNA adeno-associated virus (AAV). SLC5A3 silencing, myo-inositol depletion, Akt-mTOR inactivation and apoptosis induction were detected in SLC5A3 shRNA virus-injected NSCLC xenograft tissues. Together, elevated SLC5A3 promotes NSCLC cell growth possibly by maintaining myo-inositol contents and promoting Akt-mTOR activation.

Clinical significance of serum IgM and IgG levels in COVID-19 patients in Hubei Province, China.

Background: There have been many studies about coronavirus disease 2019 (COVID-19), but the clinical significance of quantitative serum severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-specific IgM and IgG levels of COVID-19 patients have not been exhaustively analyzed. We aimed to investigate the time profiles of these IgM/IgG levels in COVID-19 patients and their correlations with clinical features. Methods: A multicenter clinical study was conducted from February 20 to March 5 2020. It involved 179 COVID-19 patients (108 males and 71 females) from five hospitals in Huangshi in Hubei Province, China. To detect SARS-CoV-2-specific IgM/IgG, quantitative antibody assays (two-step indirect immunoassays with direct chemiluminescence technology) based on the nucleocapsid protein (NP) and spike protein 1 (S1) were used. For normally distributed data, means were compared using the t-test, χ 2-test, or exact probability method. For categorical data, medians were compared using Mann-Whitney U test. Results: The median age was 57 (44-69) years (58 [38-69] for males and 57 [49-68] for females). The median duration of positive nucleic acid test was 22.32 (17.34-27.43) days. The mortality rate was relatively low (3/179, 1.68%). Serum SARS-CoV-2-specific IgG was detected around week 1 after illness onset, gradually increased until peaking in weeks 4 and 5, and then declined. Serum IgM peaked in weeks 2 and 3, then gradually declined and returned to its normal range by week 7 in all patients. Notably, children had milder respiratory symptoms with lower SARS-CoV-2-specific IgM/IgG levels. The duration of positive nucleic acid test in the chronic obstructive pulmonary disease (COPD) group was 30.36 (18.99-34.76) days, which was significantly longer than that in the non-COPD group (21.52 [16.75-26.51] days; P = 0.025). The peak serum SARS-CoV-2-specific IgG was significantly positively correlated with the duration of positive nucleic acid test. The incidence rate of severe and critical cases in the IgMhi group (using the median IgM level of 29.95 AU/mL as the cutoff for grouping) was about 38.0% (19/50), which was twice as much as that in the IgMlo group (18.4%; 9/49). The patients with positive chest imaging and lymphocytopenia (<1 × 109/L) had a higher SARS-CoV-2-specific IgM level. Conclusions: Quantitative SARS-CoV-2-specific IgM and IgG levels are helpful for the diagnosis, severity classification, and management of COVID-19 patients, and they should be monitored in each stage of this disease.

Cell-free DNA from bronchoalveolar lavage fluid (BALF): a new liquid biopsy medium for identifying lung cancer.

BACKGROUND: Differentiating malignant lung tumors from benign pulmonary nodules is a great challenge. While the analysis of bronchoalveolar lavage fluid (BALF) is used for diagnosing infections and interstitial lung diseases, there is limited evidence to support its use for lung cancer diagnosis. This study aimed to interrogate the potential of using BALF cell-free DNA (cfDNA) to discriminate malignant lesions from benign nodules. METHODS: Fifty-three patients with solid pulmonary nodules (≤2 cm) were prospectively enrolled, including 21 confirmed with benign disease and 32 with malignant tumors. Mutations were profiled for 30 tumor tissues and 40 BALFs. Paired BALFs and plasma from 48 patients underwent DNA methylation profiling. A methylome-based classification model was developed for BALF and plasma separately. RESULTS: Among the 30 patients with paired tissues and BALFs, 96.7% and 70% had alterations detected from their tissues (79 alterations) and BALFs (53 alterations), respectively. Using tissues as references, BALFs revealed 14 new alterations and missed 41. BALF mutation displayed a sensitivity of 71%, specificity of 77.8%, and accuracy of 72.5% in detecting lung cancer. BALF methylation achieved an accuracy of 81.3%, with both sensitivity and specificity being 81%. Plasma methylation showed a 66.7% sensitivity, 71.4% specificity, and 68.8% accuracy. BALF methylation also demonstrated 82.4% sensitivity in stage I patients. Parallel bronchoscopy, lavage cytology, and bronchial brushing demonstrated an inferior sensitivity of 23%, 3.1%, and 9.7%, respectively, compared with BALF methylation and mutation (P<0.0001). CONCLUSIONS: BALF cfDNA can serve as a liquid biopsy media for both mutation and methylation profiling, demonstrating better sensitivities in distinguishing small malignant tumors from benign nodules than conventional methods. KEYWORDS: Lung cancer diagnosis; pulmonary nodule; bronchoalveolar lavage fluid (BALF); methylation; genomic mutation.

Transformation of Two Cases of Lung Adenocarcinoma into Pulmonary Sarcomatoid Carcinoma following Treatment.

Accumulating evidence shows that histologic transformation is involved in the drug resistance of lung cancer. Moreover, it is common for lung adenocarcinoma to transform into small-cell lung cancer or squamous cell carcinoma; however, clinical cases with sarcomatoid transformation have been rarely reported. Thus, both the diagnosis and treatment of lung adenocarcinoma with sarcomatoid transformation remain difficult. Here, we discuss two patients with lung adenocarcinoma with sarcomatoid transformation-analyzing the diagnosis, clinical features, immunohistochemical characteristics, therapy, and prognosis-with the hope that this report will be used as a reference for future treatment of these patients.

New treatment of bronchopleural fistula following surgical resection of the dorsal segment of the left lower lobe: A case report.

Anatomical segment-based or subsegmental resection for early lung cancer surgery has been used in selected cases, although postoperative complications of bronchopleural fistula sometimes occur. Persistent air leaks can cause complications such as empyema and aspiration pneumonia, resulting in prolonged patient hospitalization. The traditional treatment for postoperative bronchopleural fistula is reoperation, but the advent of bronchoscopic interventional therapy usually prevents patients from needing a second operation. This article details a case of thoracoscopic segmentectomy of the left lower lung dorsal segment resulting in residual subsegmental pleural fistula, and because the use of pleural adhesives made the patient's fistula inappropriate for surgical repair, we finally used bronchoscopic injury of the airway mucosa combined with an absorbable gelatin sponge and an autologous blood closure method for successful treatment.

TRIM37 targets AKT in the growth of lung cancer cells.

BACKGROUND: TRIM37 is an ubiquitin E3 ligase. Growing evidence has demonstrated the high value of TRIM37 as a potential biomarker for diagnosis of certain cancers. However, the biological function of TRIM37 in lung cancer is still unknown. MATERIALS AND METHODS: In order to gain a deep insight into the function of TRIM37 in lung cancer cells, in the present study lentiviral vector was used to mediate RNA interference and overexpression of TRIM37 in lung cancer cells (H292, H358, and H1299). In addition, a specific AKT inhibitor LY294002 was utilized to examine the correlation between the expression of TRIM37 and AKT. RESULTS: TRIM37 acts as a positive regulator of cell proliferation in lung cancer cells. Moreover, cell apoptosis analyses showed the antiapoptosis function of TRIM37, which was mainly dependent on the regulation of BCL2 and BAX. Our results also indicated that AKT might be a target of TRIM37 in lung cancer cells. CONCLUSION: This research not only helps in understanding the molecular mechanisms of TRIM37 in detail but also provides evidence to develop novel biomarkers for lung cancer diagnosis.

A study on mother-to-fetus/infant transmission of influenza A(H7N9) virus: Two case reports and a review of literature.

OBJECTIVES: The prevention strategies for mother-to-fetus/infant transmission of H7N9 virus have not been well understood, and the study on this subject will provide further insights. METHODS: Reverse transcriptase polymerase chain reaction assay was undertaken to detect H7N9 virus in samples from a pregnant women, a postpartum woman, and their fetus/infant. Pathological features of tissues from the dead fetus were evaluated with hematoxylin and eosin staining. Hemagglutination inhibition assay was used to detect virus-specific antibodies. Furthermore, relevant literatures were reviewed and analyzed. RESULTS: A 28-year-old pregnant woman was hospitalized for H7N9 infection and prescribed with oseltamivir and peramivir for 2 days before admission. The fetal heart beating stopped on day 4, the dead fetus was delivered on day 13, and the woman expired on day 26. All fetal tissues were H7N9 virus-negative. A 28-year-old woman delivered a newborn on December 20, 2016. Five days later, she developed influenza-like symptoms and was confirmed with H7N9 infection. She had close contact with her infant for 9 days. Oseltamivir and peramivir were prescribed within 2 days after illness onset. A throat swab and a pair of serum samples from the infant were all negative for H7N9 virus during 4-week follow-up. In total, ten studies referring to transplacental transmission and four reports on maternal infection of H7N9 virus were reviewed and analyzed. CONCLUSION: No evidence showed H7N9 virus infection in both fetus and infant. The early administration of neuraminidase inhibitor seemed beneficial in preventing mother-to-fetus/infant transmission of H7N9 virus.

Knockdown of Rhotekin 2 expression suppresses proliferation and induces apoptosis in colon cancer cells.

Colon cancer is one of the most common malignant tumors in the human body, ranking second as a gastrointestinal tumor. It has a high incidence in Europe, America and China and more than 1 million new cases of colon cancer are reported worldwide each year. The incidence of colon cancer in China has increased from 12/0.1 million in the early 1970s to 56/0.1 million at present with an annual growth rate of 4.2%, which far exceeds the international level (2%). Rhotekin (RTKN) 2, a Rho-guanosine triphosphatase (GTPase) effector, has been reported to be anti-apoptotic. However, the molecular mechanism underlying the biological function of RTKN2 in colon cancer remains unknown. The present study investigated whether the mRNA expression level of RTKN2 was markedly higher in 30 human colon cancer specimens compared with adjacent non-cancerous tissues. The results showed that the protein expression level of RTKN2 was significantly higher in SW480 and HCT116 cells, compared with HIEC cells. Knockdown of RTKN2 in the SW480 and HCT116 colon cancer cells, by lentivirus-mediated RNA interference led to the notable inhibition of cell proliferation and cell cycle progression, by reducing the expression levels of the PCDA, Cyclin D1 and c-myc cell cycle-associated proteins. The inhibitory effect of RTKN2 silencing on the proliferation of colon cancer cells may be partially realized by inhibiting the Wnt/ß-catenin signaling pathway. Furthermore, the silencing of RTKN2 in the cells induced apoptosis by reducing the expression level of Bax and increasing the expression level of Bcl2. These results show that RTKN2 is involved in the carcinogenesis and progression of human colon cancer, indicating that RTKN2 may be a molecular target in colon cancer therapy.

Expression of CD40/CD40L in colon cancer, and its effect on proliferation and apoptosis of SW48 colon cancer cells.

PURPOSE: To study was to study the expression of CD40/CD40L in colon cancer and investigate the effects of CD40/CD40L overexpression on the proliferation and apoptosis of SW48 colon cancer cell line. METHODS: Immunohistochemistry was used to detect the expression of CD40 protein in colon cancer tissue samples from 70 patients, and 10 adjacent normal tissue samples. A CD40L gene-containing plasmid was transfected into SW48 colon cancer cells using lipofectamine 2000. Cell proliferation was measured by MTT assay. The expression of CD40/CD40L was measured by real-time PCR (RT-PCR). Protein expression of Bcl-2 and Bax was detected by Western blot. RESULTS: Immunohistochemical analysis showed that CD40 was mainly expressed in the cell membrane and scarcely in the cytoplasm. The expression of CD40 in colorectal cancer tissue was significantly higher than in normal adjacent tissue. RT-PCR showed that CD40 was highly expressed in SW48 cells. The expression of CD40L mRNA was significantly increased in SW40 cells transfected with the CD40L gene-containing plasmid (p<0.01). MTT assay showed that the activity of CD40L transfected cells was significantly inhibited compared with control cells transfected with empty plasmid (p<0.01). Western blot analysis demonstrated significantly decreased Bcl-2 expression, and significantly increased Bax expression in cells transfected with the CD40L gene-containing plasmid compared with the control cells (p<0.01). CONCLUSION: In conclusion, CD40 protein expression was significantly higher in colon cancer tissue compared with normal tissue, and the apoptosis of SW48 colon cancer cells can be induced by CD40L gene transfection.

The prognostic value of interleukin-17 in lung cancer: A systematic review with meta-analysis based on Chinese patients.

BACKGROUND: Interleukin-17 (IL-17) plays an important role in cancer progression. Previous studies remained controversial regarding the correlation between IL-17 expression and lung cancer (LC) prognosis. To comprehensively and quantitatively summarize the prognostic value of IL-17 expression in LC patients, a systematic review and meta-analysis were performed. METHODS: We identified the relevant literatures by searching the PubMed, EMBASE, Cochrane Library, SinoMed, China National Knowledge Infrastructure (CNKI) and Wanfang Data databases, up until April 1, 2017. Overall survival (OS), disease free survival (DFS) and clinicopathological characteristics were collected from relevant studies. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated to estimate the effective value of IL-17 expression on clinical outcomes. RESULTS: Six studies containing 479 Chinese LC patients were involved in this meta-analysis. The results indicated high IL-17 expression was independently correlated with poorer OS (HR = 1.82, 95% CI 1.44-2.29, P < 0.00001) and shorter DFS (HR = 2.41, 95% CI 1.42-4.08, P = 0.001) in LC patients. Further, when stratified by LC histological type (non-small cell lung cancer and small cell lung cancer), tumor stage (Ⅰ-Ⅲ,Ⅰ-Ⅳ and Ⅳ), detection specimen (serum, intratumoral tissue and pleural effusion), test method (immunological histological chemistry and enzyme linked immunosorbent assay), and HR estimated method (reported and estimated), all of the results were statistically significant. These data indicated that elevated IL-17 expression is correlated with poor clinical outcomes in LC. The meta-analysis did not show heterogeneity or publication bias. CONCLUSIONS: The present meta-analysis revealed that high IL-17 expression was an indicator of poor prognosis for Chinese patients with LC. It could potentially help to assess patients' prognosis and estimate treatment efficacy in therapeutic interventions.

Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Increases the Yield of Transbronchial Lung Biopsy for the Evaluation of Peribronchial Lesions.

BACKGROUND: Due to absence of visible endobronchial target, the diagnostic yield of flexible bronchoscopy for peribronchial lesions has been unsatisfactory. Convex probe endobronchial ultrasound (CP-EBUS) has allowed for performing real-time transbronchial needle aspiration (TBNA) of enlarged hilar and mediastinal lymph nodes and therefore could also be used as a means of diagnosing proximal peribronchial lesions. METHODS: We retrospectively analyzed the results related to 72 patients who underwent CP-EBUS for peribronchial lesions without endobronchial involvement and adjacent to three-grade bronchi based on chest computed tomography (CT) scan. We recorded the images during EBUS as well as the diagnostic results of TBNA and conventional-transbronchial lung biopsy/brush (C-TBLB/b), and final diagnoses were based on pathologic analysis and follow-up. RESULTS: In all cases, the mass was able to be identified using EBUS in 97.2% patients (70/72) who were performed with EBUS-TBNA + C-TBLB/b. Sixty-six patients had a final diagnosis, 80.0% patients (56/70) had malignancies, and 14.3% patients (10/70) had benign disease. In malignancies, the diagnostic yield of C-TBLB/b was 57.1% (32/56) and in EBUS-TBNA was 85.7% (48/56), whereas pathologic diagnosis reached 94.6% when EBUS-TBNA was combined with C-TBLB/b. C-TBLB/b + EBUS-TBNA also exhibited stronger potency of histolytic diagnosis for malignancies than either EBUS-TBNA or C-TBLB/b alone. Furthermore, there are data supporting the value of EBUS-TBNA for the diagnosis of benign lung disease. CONCLUSION: The combined endoscopic approach with EBUS-TBNA and C-TBLB/b is an accurate and effective method for the evaluation of peribronchial lesions, with better results than using each technique alone.

Enhanced suppression of polyclonal CD8+25+ regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes.

Compared with CD4+25+ regulatory T cells (Tregs), the mechanisms for natural, polyclonal CD8+25+ Treg immune suppression have been significantly less studied. We previously showed that polyclonal T cells can acquire antigen-specific targeting activity through arming with exosomal peptide-MHC (pMHC). In this study, we assessed the suppressive effect of CD8+25+ Tregs or CD8+25+ Tregs armed with ovalbumin (OVA)-specific exosomes on other immune cells and OVA-specific dendritic cell (DCOVA)-stimulated antitumor immunity. We demonstrate that CD8+25+ Tregs inhibit T cell proliferation in vitro in a cell contact-dependent fashion but independent of the expression of immunosuppressive IL-10, TGF-ß, and CTLA-4. CD8+25+ Tregs anergize naïve T cells upon stimulation by up-regulating T cell anergy-associated Egr2 and down-regulating IL-2 production. Tregs also anergize DCs by preventing DC maturation through the down-regulation of Iab, CD80, CD86, and inflammatory cytokines, leading to defects in T cell stimulation. Moreover, CD8+25+ Tregs inhibit CTLs through inducing CTL death via perforin-mediated apoptosis and through reducing effector CTL cytotoxic activity via down-regulating CTL perforin-production and degranulation. In addition, we show that CD8+25+ Tregs suppress DCOVA-stimulated CTL responses in priming and effector phases and inhibit immunity against OVA-expressing CCLOVA lung cancer. Remarkably, polyclonal CD8+25+ Tregs armed with OVA-specific exosomal pMHC class-II (pMHC-II), or pMHC class-I (pMHC-I) complexes exert their enhanced inhibition of CTL responses in the priming and the effector phases, respectively. Taken together, our investigation reveals that assigning antigen specificity to nonspecific polyclonal CD8+25+ Tregs for enhanced immune suppression can be achieved through exosomal pMHC arming. This principle may have a great effect on Treg-mediated immunotherapy of autoimmune diseases.

Soluble CD40 in plasma and malignant pleural effusion with non-small cell lung cancer: A potential marker of prognosis.

OBJECTIVE: Soluble CD40 (sCD40) is a potential modulator for both antitumor responses and CD40-based immunotherapy; however the levels and significance of sCD40 in non-small cell lung cancer (NSCLC) patients with malignant pleural effusion are unknown. METHODS: Forty-eight patients with lung cancer were treated in our institutions from January 2008 to January 2010. Peripheral blood and pleural effusion samples were collected from each subject. sCD40 levels in plasma and malignant pleural effusions supernatant were measured. The CD40L expression on CD3t T-cells was confirmed by flow cytometric direct immunofluorescence analysis. All patients were followed up after the study ended on January 1, 2010. RESULTS: Patients with malignant pleural effusion of NSCLC had elevated circulating and pleural effusion levels of sCD40, and these elevated sCD40 levels were associated with advanced diseases and a poor prognosis. CONCLUSIONS: These findings indicate that elevated sCD40 may have a role in modulating antitumor responses and may also be a useful prognostic marker.

Association between single nucleotide polymorphism of PD-L1 gene and non-small cell lung cancer susceptibility in a Chinese population.

AIM: To evaluate the correlation between a polymorphism of PD-L1 gene and the susceptibility of non-small cell lung cancer (NSCLC) in a Chinese population. METHODS: A total of 293 Chinese patients with NSCLC and 293 age and sex matched controls of the same ethnic origin were enrolled in this study. A/C polymorphism at position 8923 in intron 4 of PD-L1 gene was typed using the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). The interactions between A/C genotype, allele frequency and NSCLC susceptibility were analyzed. RESULTS: The A/C genotype frequencies were significantly different between NSCLC patients and controls. The AC and CC frequencies were higher in NSCLC patients than in controls (16.4 vs 8.9%, 1.0 vs 0.3%, respectively). The C-allele frequency was higher in NSCLC patients than in controls (9.2 vs 4.8%). Significant differences in the A and C allele frequencies were noted between the two groups (χ(2) = 8.864, P = 0.003). More risk of NSCLC was found in individuals carrying the C allele than in those carrying the A allele (OR = 2.203; 95% CI 1.262-3.242). In both light smokers (≤20 pack-years) and heavy smokers (>20 pack-years), individuals carrying the C-allele had more risk of NSCLC than those carrying the A-allele (light smokers OR = 1.847, 95% CI 1.001-3.409; heavy smokers OR = 3.252, 95% CI 1.196-8.845, respectively). CONCLUSION: An A/C polymorphism at position 8923 in the PD-L1 gene is associated with NSCLC susceptibility. The PD-L1 polymorphism plays a role in NSCLC, especially in patients with the C-allele.

Clinical significance of the induction of macrophage differentiation by the costimulatory molecule B7-H3 in human non-small cell lung cancer.

B7-H3, a member of the B7 family of molecules, is expressed in certain types of human cancer and is important in tumor development and progression. Although several studies have reported that the expression of B7-H3 is correlated with poor outcomes in patients with cancer, its exact role in cancer remains unknown. In the present study, the expression levels of B7-H3 in the pathological specimens of 105 patients treated for non-small cell lung cancer (NSCLC) were examined by immunohistochemistry. A high expression level of B7-H3 was observed in 46.9% of the 105 NSCLC tissue specimens. These patients demonstrated a more advanced tumor grade and a shorter survival time. In addition, we also examined the levels of tumor-associated macrophages (TAMs) in NSCLC tissues and observed that the levels were positively correlated with the expression of B7-H3, and that higher levels of macrophages were associated with lower levels of infiltrating T cells and a shorter survival time. These results demonstrated that TAMs are important in the evasion of tumor immune surveillance in NSCLC. Furthermore, through knockdown of B7-H3 by RNA interference, we observed that soluble B7-H3 was capable of inducing macrophages to express higher levels of macrophage mannose receptor (MMR) and lower levels of human leukocyte antigen (HLA)-DR, as well as higher levels of interleukin-10 (IL-10) and lower levels of IL-1ß in vitro. These observations are characteristic of an anti-inflammatory/reparatory (alternative/M2) phenotype. Therefore, our data suggests that B7-H3 proteins are involved in the progression of NSCLC by inducing the development of monocytes into anti-inflammatory cells.

Endothelial cell protein C receptor (EPCR) is expressed by lung carcinoma and correlated with clinical parameters.

BACKGROUND: Endothelial cell protein C receptor (EPCR) is a cellular receptor for protein C and activated protein C (APC). In view of convincing evidence, it seems that EPCR, beyond its effects on coagulation and inflammation, could interfere with carcinogenesis. METHODS: In the present study, we investigated EPCR expression in 60 lung carcinoma tissues and 37 para-carcinoma tissues, and analyzed the relationship between EPCR expression and histopathological parameters, clinical parameters, and vascular density. RESULTS: In vitro, culturing lung cancer cell lines constitutively expressed EPCR at the level of mRNA and protein. The pathologic results clearly demonstrated that EPCR expression, including membranous and cytoplasmic staining, was significantly higher in carcinoma than that in the para-carcinoma tissues. The EPCR expression was therefore related to tumor size, lymph node metastasis as well as TNM stage. The expression of EPCR was also significantly correlated with microvessel density (MVD). CONCLUSIONS: These observations provide evidence that EPCR may be involved in the carcinogenesis of lung cancer. It is suggested that EPCR may be a useful biomarker for evaluating the clinical status of lung cancer.

Induced expression of B7-H4 on the surface of lung cancer cell by the tumor-associated macrophages: a potential mechanism of immune escape.

B7-homolog 4 (B7-H4), a recently identified homolog of B7.1/2 (CD80/86), has been described to exert co-stimulatory and immune regulatory functions. We investigated the expression and the functional activity of B7-H4 in lung cancer in vitro and in vivo. Although a lung cancer cell line constitutively expressed B7-H4 mRNA and protein in plasma, primary tumor cell isolated from the transplanted lung carcinoma model expressed B7-H4 on the surface. Interestingly, in transplanted lung carcinoma model, the expression of membrane-bound B7-H4 in tumor cells was increased as prolonging of tumor transformation. Exposure to tumor-associated macrophages strongly induced membrane-bound B7-H4 expression on the lung cancer cell line. To elucidate the functional significance of lung cancer-related B7-H4 expression, we performed co-culture experiments of lung cancer cell with allo-reactive T cells. Lung cancer-related B7-H4 was identified as a strong inhibitor of T-cell effect. Furthermore, B7-H4 mAb had an ability to inhibit tumor growth in vivo. B7-H4 expression may thus significantly influence the outcome of T-cell tumor cell interactions and TAM induced membrane-bound B7-H4 on the lung cancer cell represents a novel mechanism by which lung cancer cells evade immune recognition and destruction.