Effectiveness and safety of chemotherapy with cytokine-induced killer cells in non–small cell lung cancer: A systematic review and meta-analysis of 32 randomized controlled trials

Background aims

Cytokine-induced killer (CIK) cells are the most commonly used cellular immunotherapy for multiple tumors. To further confirm whether chemotherapy with CIK cells improves clinical effectiveness and to reveal its optimal use in non–small cell lung cancer (NSCLC), we systematically reevaluated all relevant studies.

Clinical effect and safety of dendritic cell–cytokine-induced killer cell immunotherapy for pancreatic cancer: a systematic review and meta-analysis

BackgroundAlthough promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical effect and safety are associated with some controversy, and lack sufficient evidence. Here, we conducted a meta-analysis of 21 clinical trials to better evaluate the efficacy of DC-CIK immunotherapy in clinical practice to treat PC.MethodsPubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform (WANFANG Data) were searched to identify clinical trials that used DC-CIK immunotherapy for PC. Meta-analysis was performed using RevMan 5.3 and Stata 12.0.ResultsA total of 21 clinical trials involving 1549 patients were included. Compared with traditional treatment, DC-CIK immunotherapy improved and increased the clinical indices such as complete remission, partial remission, overall response rate, disease control rate, overall survival (0.5-y OS, 1-y OS, 1.5-y OS, 2-y OS and 3-y OS), interferon γ and CD3+, CD4+, CD4+/CD8+ and CD3+CD56+ lymphocyte. Additionally, DC-CIK immunotherapy reduced stable disease, progression disease, mortality, CD8+, CD4+CD25+CD127 low lymphocyte and interleukin-4. Furthermore, it showed a low incidence of adverse reactions (22%).ConclusionIn contrast to traditional therapy, DC-CIK immunotherapy not only shows improved short-term effect, long-term effect and immunologic function, but also reduces mortality and negative immunoregulatory index, and shows mild adverse reactions. This is the first study to evaluate the clinical effect and safety of DC-CIK immunotherapy for PC, and it indicated that DC-CIK immunotherapy may be suitable for patients with advanced PC or intolerance to radiotherapy and chemotherapy.     

Effect of dendritic cell–based immunotherapy on hepatocellular carcinoma: A systematic review and meta-analysis

Background aims

Dendritic cell (DC)-based immunotherapy has recently been reported frequently in the treatment of hepatocellular carcinoma (HCC); however, its efficacy remains controversial. In this study, we aimed to evaluate the clinical efficacy of DC-based immunotherapy on HCC by conducting a systematic review and meta-analysis.

Global estimate of gastric cancer in Helicobacter pylori–infected population: A systematic review and meta-analysis

There is information regarding the rates of gastric cancer (GC) in different populations and the important role of Helicobacter pylori in GC development; however, no comprehensive study has yet been performed to investigate the prevalence of GC in H. pylori–infected patients. PubMed, Embase, and Cochrane Library through January 1, 2000 were searched without language restrictions. Quality of included studies was assessed with a critical appraisal checklist recommended by the Joanna Briggs Institute. All of the analyses were conducted using Comprehensive Meta-Analysis Software Version 2.0 and Stata 14.0. Forty-four studies from 17 countries were included. The pooled frequency of GC was 17.4% (95% confidence interval: 16.4–18.5) in H. pylori–infected population. The frequency of GC among H. pylori–infected population varied markedly across countries. The highest rate of GC was observed in H. pylori–infected individuals from Asian countries. The frequency of GC was relatively high in H. pylori–infected population in the world. However, the eradication of H. pylori might be a promising strategy for GC prevention, especially in high-risk populations such as Asian countries.     

Serum macrophage inhibitory cytokine-1 as a clinical marker for non–small cell lung cancer

The aim of this study was to investigate the value of serum macrophage inhibitory factor-1 (MIC-1) level in patients with non–small cell lung cancer (NSCLC). Serum samples from 296 patients with NSCLC and 240 healthy controls were collected. The levels of serum MIC-1 were determined by ELISA. The serum MIC-1 levels in NSCLC patients were higher than that of the controls (P <.001). Univariate and multivariate Cox regression analysis showed that serum MIC-1 was an independent prognostic indicator of OS and PFS. Serum MIC-1 is a valuable biomarker for the diagnosis and prognosis of NSCLC.     

Serum tumour M2-pyruvate kinase as a biomarker for diagnosis and prognosis of early-stage non–small cell lung cancer

Tumour M2-pyruvate kinase (TUM2-PK) is up-regulated in many human cancers. This study was to evaluate the clinical value of serum TUM2-PK in early-stage non–small cell lung cancer (NSCLC) patients. A total of 162 consecutive early-stage NSCLC patients were enrolled and followed up after tumour resection. Serum TUM2-PK level was detected by enzyme-linked immunosorbent assay (ELISA) in NSCLC patients, 50 benign pulmonary disease patients and 102 healthy controls. The TUM2-PK level in NSCLC patients was higher than that of healthy controls (P < .001) and benign pulmonary disease patients (P < .001). A threshold of 30 U/mL could be used to diagnose early-stage NSCLC with 71.6% sensitivity and 98.0% specificity. The 5-year overall survival rate in patients with high TUM2-PK level was lower than that of patients with low TUM2-PK level (P = .009). Multivariable Cox regression showed that high TUM2-PK level was an independent risk factor for overall survival (HR = 2.595, 95% CI: 1.231-5.474, P = .012). High serum TUM2-PK level could be a potential biomarker for diagnosis and prognosis of early-stage NSCLC patients.     

Efficacy of cascade-primed cell infusion as an adjuvant immunotherapy with concurrent chemotherapy for patients with non–small-cell lung cancer: A retrospective observational study with a 5-year follow-up

BackgroundClinical studies have shown the efficacy of combination therapy for various malignancies. In this study, the characteristics, safety and feasibility of use of cascade-primed (CAPRI) cells for the combination treatment of non–small-cell lung cancer (NSCLC) were evaluated both in vitro and in vivo.MethodsSixty-five patients with stage II–IV NSCLC were recruited. Of these patients, 31 patients received CAPRI cell therapy combined with chemotherapy (CAPRI group), and the other 34 patients constituted the control group and received chemotherapy alone. This study primarily aimed to evaluate the overall survival (OS), progression-free survival (PFS), short-term responses and treatment efficacy.ResultsCD83, CD1a, CD80 and CD86 marker levels were significantly upregulated in CAPRI cells. Interferon-γ expression levels were highest in CD3⁺CD8⁺ cells (33.77% ± 4.40%). Furthermore, interleukin-2 levels were highest in CD3⁺CD56⁺ cells (26.73% ± 6.63%), whereas perforin expression levels were similar in CD3⁺CD8⁺ and CD3⁺CD56⁺ cells. Furthermore, CAPRI cells had a better anti-tumor potential in CD3⁺CD56⁺ cells and displayed the highest expression levels of CD107a to H460 and A549 cell lines. The 5-year OS was significantly greater in the CAPRI group than in the control group (P = 0.008), and the PFS of two groups exhibited a significant difference (P = 0.007). Median OS (48 versus 31.6 months; P = 0.004) and PFS (48 versus 36.4 months; P = 0.016) differed between these two groups. Moreover, treatment-associated toxicities were mild and well-tolerated by patients with NSCLC.ConclusionCAPRI cell therapy potentially prolongs the survival of patients with NSCLC when combined with chemotherapy.     

Interaction of estrogen receptor β5 and interleukin 6 receptor in the progression of non–small cell lung cancer

Numerous studies have shown that the estrogen receptor beta (ERβ) and interleukin 6 receptor (IL-6R) had interaction in many tumors, including lung cancer. Previous studies found that ERβ5 exhibits a different biological function compared with the other subtypes of ERβ. Therefore, this study mainly explores the interaction between ERβ5 and IL-6R in the progression of lung cancer. We found that the expression of ERβ5, IL-6 and glycoprotein 130 (GP130) were significantly increased (P < 0.001) and the 5-year survival rate with the co-expression of ERβ5 and GP130 is significantly lower (P = 0.0315) in non-small cell lung cancer (NSCLC) patients. The cell proliferation, invasion, and cell cycle were markedly increased, and the cell apoptotic was markedly inhibited with the concurrent action of ERβ5 and IL-6 in A549 cells (P < 0.05). In addition, the expression of ERβ5, GP130, p-AKT, and p-44/42 MAPK was also significantly increased in A549 cells (P < 0.05). These results indicate that ERβ5 and GP130 can synergistically promote the progression of NSCLC and maybe combined as an independent prognostic factor in patients. In addition, these results also provide a theoretical basis for the combined targeting therapy of ERβ5 and GP130 in NSCLC.     

ZCCHC14 regulates proliferation and invasion of non–small cell lung cancer through the MAPK-P38 signalling pathway

ZCCHC14 is a CCHC-type zinc finger protein which is expressed in tissues in human and mouse. The function of ZCCHC14 in tumours remains unclear. In this research, we explored the expression, function and related molecular mechanisms of ZCCHC14 in human non–small cell lung cancer (NSCLC). Immunochemistry staining showed that ZCCHC14 was low-expressed or absent in NSCLC tissues. In NSCLC patients, the low expression of ZCCHC14 in tumour tissues was significantly correlated with TNM stage, differentiation degree and adverse clinical outcome (P < .05). The proliferation and invasion ability of cancer cells transfected with ZCCHC14 CRISPR/Ca9 KO plasmids was significantly enhanced (P < .05). Immunoblotting analysis indicated that the expression of p-P38, cyclinD1 and MMP7 were significantly up-regulated after disabling ZCCHC14 (P < .05). We used MAPK-P38 pathway inhibitor doramapimod (BIRB 796) to inhibit P38 signalling pathway activity and determined that the agent significantly disrupted the function of ZCCHC14 and hindered the proliferation and invasion of the tumour. The finding revealed that ZCCHC14 can regulate proliferation and invasion of NSCLC through the P38 pathway. ZCCHC14 plays a crucial regulatory role in the development of NSCLC and may become a zinc finger target for clinical treatment.     

The increased expression and aberrant methylation of SHC1 in non–small cell lung cancer: Integrative analysis of clinical and bioinformatics databases

Despite the previous evidence showing that SHC adaptor protein 1 (SHC1) could encode three distinct isoforms (p46SHC, p52SHC and p66SHC) that function in different activities such as regulating life span and Ras activation, the precise underlying role of SHC1 in lung cancer also remains obscure. In this study, we firstly found that SHC1 expression was up-regulated both in lung adenocarcinoma (LUAD) and in lung squamous cell carcinoma (LUSC) tissues. Furthermore, compared to patients with lower SHC1 expression, LUAD patients with higher expression of SHC1 had poorer overall survival (OS). Moreover, higher expression of SHC1 was also associated with worse OS in patients with stages 1 and 2 but not stage 3 lung cancer. Significantly, the analysis showed that SHC1 methylation level was associated with OS in lung cancer patients. It seemed that the methylation level at specific probes within SHC1 showed negative correlations with SHC1 expression both in LUAD and in LUSC tissues. The LUAD and LUSC patients with hypermethylated SHC1 at cg12473916 and cg19356022 probes had a longer OS. Therefore, it is reasonable to conclude that SHC1 has a potential clinical significance in LUAD and LUSC patients.     

Association of single nucleotide autophagy-related protein 5 gene polymorphism rs2245214 with susceptibility to non–small cell lung cancer

Introduction : Autophagy is a mechanism that is involved in the regulation of cellular life, apoptosis, and stemness while its intervening genes play important functions in various cancers including lung cancer. ATG5 is one of the key genes for the regulation of the autophagy pathway. In this study, our team has investigated the potential relationship between ATG5 gene polymorphism rs2245214 with non–small cell lung cancer (NSCLC) in a subpopulation of patients from southern Iran. In this study, 34 patients with NSCLC (20 males and 14 females [mean age: 12.86 ± 60.47 years]) and 50 healthy subjects (30 males and 20 females [mean age: 13.09 ± 56.62 years]) were studied in terms of the genotype of the ATG5 gene. We used restriction fragment length polymorphism and analyzed the results using SPSS software (v.23). The results revealed that subjects harboring the guanine/cytosine (GC) genotype of the rs2245214 ATG5 gene polymorphism had suffered less from NSCLC, whereas the prevalence of the C-allele of this polymorphism was significantly higher in patients with NSCLC ( P < 0.05). On the basis of the results of logistic regression, the presence of this C-allele may predict the risk of lung cancer ( P value = 0.011; OR, 3.52; 95% CI, 1.33-9.26). This study concludes that the C-allele of the rs2245214 ATG5 gene polymorphism is associated with increased susceptibility to NSCLC, whereas the GC genotype of this polymorphism is associated with decreased risk and might therefore have a protective role in the development of NSCLC.     

Retracted: miR-145 modulates epithelial-mesenchymal transition and invasion by targeting ZEB2 in non–small cell lung cancer cell lines

Lung cancer is the leading cause of cancer-related deaths worldwide. Epithelial-mesenchymal transition (EMT) is a major event that drives cancer progression. Here we aim to investigate the role of microRNA, miR-145, in regulating EMT of the highly invasive non–small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction analysis indicated that miR-145 was downregulated in cancer tissue compared with that in adjacent normal tissue. NSCLC cell lines, namely H1299, PC7, and SPCA-1, also demonstrated miR-145 downregulation, which is correlated well with their invasive ability, assessed by the Matrigel invasion assay. miR-145 overexpression resulted in downregulation of N-cadherin, and downregulation of vimentin and E-cadherin, suggesting a decreased EMT activity. TargetScan analysis predicted that a binding site exists between miR-145 and an oncogene, ZEB2, which was verified using the dual-luciferase assay. Alteration of miR-145 expression also induced inverse effects on ZEB2 expression, and a negative correlation exists between ZEB2 and miR-145 in human tissues. ZEB2 and miR-145 also exerted antagonizing effects on the invasion of NSCLC cells. Therefore, miR-145 is an important molecule in NSCLC that regulates cancer EMT through targeting ZEB2.     

A panel of noncoding RNAs in non–small-cell lung cancer

Non–small-lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC could pave the way for effective therapies. Analysis of molecular genetic biomarkers in biological fluids has been proposed as a useful tool for cancer diagnosis. Here, we aimed to develop a panel of noncoding RNAs (ncRNAs) in sputum for NSCLC early detection. Expression of 11 ncRNAs were analyzed by real–time polymerase chain reaction in sputum samples of 30 NSCLC patients and 30 sex- and age-matched cancer-free controls. Stability of endogenous microRNAs (miRNAs) in sputum was evaluated after 3 and 6 days at 4°C, 6 months, and 1 year at −80°C. Nine ncRNAs showed significant differences of their expression in sputum between NSCLC patients and controls. A logistic regression model with the best prediction was built based on miR-145, miR-126, and miR-7. The composite of the three miRNAs produced 90% sensitivity and specificity in distinguishing NSCLC patients from the controls. Results indicate that miRNAs could be useful biomarkers based on their stability under various storage conditions and maintain differential changes between cancer and control groups. Moreover, measurement of miRNAs in sputum could be a noninvasive approach for detection of lung cancer.     

Grain-sized moxibustion promotes NK cell antitumour immunity by inhibiting adrenergic signalling in non–small cell lung cancer

Lung cancer is the leading cause of cancer-related death worldwide, and non–small cell lung cancer (NSCLC) accounts for 85% of lung cancer diagnoses. As an ancient therapy, moxibustion has been used to treat cancer-related symptoms in clinical practice. However, its antitumour effect on NSCLC remains largely unexplored. In the present study, a Lewis lung cancer (LLC) xenograft tumour model was established, and grain-sized moxibustion (gMoxi) was performed at the acupoint of Zusanli (ST36). Flow cytometry and RNA sequencing (RNA-Seq) were used to access the immune cell phenotype, cytotoxicity and gene expression. PK136, propranolol and epinephrine were used for natural killer (NK) cell depletion, β-adrenoceptor blockade and activation, respectively. Results showed that gMoxi significantly inhibited LLC tumour growth. Moreover, gMoxi significantly increased the proportion, infiltration and activation of NK cells, whereas it did not affect CD4⁺ and CD8⁺ T cells. NK cell depletion reversed gMoxi-mediated tumour regression. LLC tumour RNA-Seq indicated that these effects might be related to the inhibition of adrenergic signalling. Surely, β-blocker propranolol clearly inhibited LLC tumour growth and promoted NK cells, and gMoxi no longer increased tumour regression and promoted NK cells after propranolol treatment. Epinephrine could inhibit NK cell activity, and gMoxi significantly inhibited tumour growth and promoted NK cells after epinephrine treatment. These results demonstrated that gMoxi could promote NK cell antitumour immunity by inhibiting adrenergic signalling, suggesting that gMoxi could be used as a promising therapeutic regimen for the treatment of NSCLC, and it had a great potential in NK cell–based cancer immunotherapy.