Immune Infiltration In Lung Adenocarcinoma Research Articles

Tumor stemness and immune infiltration synergistically predict response of radiotherapy or immunotherapy and relapse in lung adenocarcinoma.

Cancer stem cells (CSCs) have been shown to accelerate tumor recurrence, radiotherapy, and chemotherapy resistance. Immunotherapy is a powerful anticancer treatment that can significantly prolong the overall survival of patients with lung adenocarcinoma (LUAD). However, little is known about the function of genes related to tumor stemness and immune infiltration in LUAD. After integrating the tumor stemness index based on mRNA expression (mRNAsi), immune score, mRNA expression, and clinical information from the TCGA database, we screened 380 tumor stemness and immune (TSI)‐related genes and constructed a five TSI‐specific‐gene (CPS1, CCR2, NT5E, ANLN, and ABCC2) signature (TSISig) using a machine learning method. Survival analysis indicated that TSISig could stably predict the prognosis of patients with LUAD. Comparison of mRNAsi and immune score between high‐ and low‐TSISig groups suggested that TSISig characterized tumor stemness and immune infiltration. In addition, enrichment of immune subpopulations showed that the low‐TSISig group held more immune subpopulations. GSEA revealed that TSISig had a strong association with the cell cycle and human immune response. Further analysis revealed that TSISig not only had a good predictive ability for prognosis but could also serve as an excellent predictor of tumor recurrence and response to radiotherapy and immunotherapy in LUAD patients. TSISig might regulate the development of LUAD by coordinating tumor stemness and immune infiltration. Finally, a connectivity map (CMap) analysis demonstrated that the HDAC inhibitor could target TSISig.

LncRNA ADAMTS9-AS2 is a Prognostic Biomarker and Correlated with Immune Infiltrates in Lung Adenocarcinoma.

BackgroundThe role of long noncoding RNA (LncRNA) ADAMTS9 antisense RNA 2 (ADAMTS9-AS2) is unclear in lung adenocarcinoma (LUAD). The aim of this study was to explore the relationship between ADAMTS9-AS2 and LUAD, based on The Cancer Genome Atlas (TCGA) database and bioinformatics analysis.MethodsVarious statistical methods, Kaplan–Meier method, Cox regression analysis, GSEA, and immune infiltration analysis were used to evaluate the relationship between clinical features and ADAMTS9-AS2 expression, prognostic factors, and the significant involvement of ADAMTS9-AS2 in function.ResultsIn LUAD patients, low expression of ADAMTS9-AS2 was associated with N stage (P=0.011), gender (P=0.002), number of packs smoked (P=0.024) and smoker (P<0.001). Low ADAMTS9-AS2 expression predicted a poorer overall survival (OS) (HR: 0.68; 95% CI: 0.51–0.91; P=0.01). And ADAMTS9-AS2 expression (HR: 0.626; 95% CI: 0.397–0.986; P=0.043) was independently correlated with OS in LUAD patients. Unwinding of DNA, extrinsic pathway, polo-like kinase-mediated events, cori cycle, MCM pathway, proteasome pathway, lagging strand synthesis and PCNA-dependent long patch base excision repair were differentially enriched in ADAMTS9-AS2 high expression phenotype. ADAMTS9-AS2 expression was correlated with certain immune infiltrating cells.ConclusionIn LUAD patients, ADAMTS9-AS2 expression was significantly associated with poor survival and immune infiltration. ADAMTS9-AS2 may be a promising biomarker of prognosis and response to immunotherapy for LUAD.

RAB11FIP1: An Indicator for Tumor Immune Microenvironment and Prognosis of Lung Adenocarcinoma from a Comprehensive Analysis of Bioinformatics.

Lung adenocarcinoma (LUAD) was the first one all over the world. RAB11FIP1 was found to be expressed differently in a critical way among different cancers. However, the prognostic value and immune infiltration of RAB11FIP1 expression in LUAD are unclear. In this study, the expression of RAB11FIP1 in LUAD was investigated in the Oncomine, TCGA, GEO, and UALCAN databases. Kaplan-Meier analysis was chosen to compare the association between RAB11FIP1 expression and overall survival (OS) in LUAD patients. The dataset of TCGA was used to analyze the pertinence between RAB11FIP1 and clinicpathological factors. GO, KEGG, and network analysis of protein-protein interactions (PPI) were conducted to investigate the potential mechanism of RAB11FIP1. In the end, the relevance of RAB11FIP1 to cancer-immune infiltrates was investigated. RAB11FIP1 was found to be down-regulated by tumors compared with adjacent normal tissue in multiple LUAD cohorts. RAB11FIP1 is an independent prognostic factor in lung adenocarcinoma. There was a high correlation between low RAB11FIP1 in tumors and worse OS in LUAD. Functional network analysis suggested that RAB11FIP1 was associated with multiple pathways. Besides, the expression of RAB11FIP1 was closely related to the infiltration levels of B cell, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. RAB11FIP1 expression in LUAD occurred with a variety of immune markers. Our findings suggest that RAB11FIP1 is related to prognosis and immune infiltrates in LUAD.

TPD52L2 Is a Prognostic Biomarker and Correlated With Immune Infiltration in Lung Adenocarcinoma.

Tumor protein D52-like 2 (TPD52L2) belongs to the members of the TPD52 family. TPD52L2 was reported to regulate proliferation and apoptosis in cancer cells. However, its role in lung adenocarcinoma (LUAD) was uncertain. We evaluated the expression, methylation, copy number alteration, and prognostic significance of TPD52L2 using RNA-seq data from The Cancer Genome Atlas (TCGA). Enrichment analysis of TPD52L2 was conducted using the R package “clusterProfiler.” We further assessed the association between TPD52L2 and immune cell infiltration level, immunosuppressive genes, and tumor mutational burden (TMB). The difference of gene mutant frequency in high- and low-TPD52L2 groups was also analyzed. The results showed that TPD52L2 was over-expressed and predicted worse survival status in LUAD. We also found that TPD52L2 expression was positively associated with the infiltration levels of immunosuppressive cells, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and negatively correlated with immune killer cells, such as CD8+ T and NK cells in pan-cancer, including LUAD. In addition, TPD52L2 expression was associated with immunosuppressive genes and TMB. High expression of TPD52L2 was with more mutant frequency of TP53. In summary, our results show that TPD52L2 is an oncogene and a potential prognostic biomarker in LUAD. High TPD52L2 expression is a possible indicator of immune infiltration and associated with tumor immunosuppressive status in LUAD.

The correlation of WDR76 expression with survival outcomes and immune infiltrates in lung adenocarcinoma.

BackgroundWD repeat domain 76 (WDR76) is a predicted member of the WD40-repeat-containing domain superfamily and possibly involves in various biological processes, but its function in cancers is poorly characterized. This study aimed to evaluate the role of WDR76 in the prognosis and immune infiltrates of lung adenocarcinoma (LUAD).MethodsWDR76 expressions in LUAD tissues and normal tissues were primarily compared by The Cancer Genome Atlas (TCGA) database, and were validated in cohorts from Gene Expression Omnibus (GEO) database. The associations between WDR76 expression and clinicopathologic characteristics were analyzed. Kaplan–Meier and Cox regression analyses were performed to determine the impact of WDR76 expression on survival outcomes. The protein interaction network of WDR76 was built using STRING website. TIMER and GEPIA databases were used to investigate the correlation between WDR76 expression and immune infiltrates.ResultsWDR76 expression was elevated in LUAD (P < 0.001) and high WDR76 expression was associated with advanced N stage, M stage and pathologic stage. Expectedly, high WDR76 expression significantly correlated with poor survival outcomes and was the independent risk factor for overall survival (OS) (HR 1.468, 95% CI [1.031–2.089], P = 0.033) and disease specific survival (DSS) (HR 1.764, 95% CI [1.095–2.842], P = 0.020). DDB1 and LSH were the important proteins interacting with WDR76. WDR76 expression correlated with CD8+ T cells presence and was also positively associated with levels of inhibitory receptors.ConclusionWDR76 expression was involved in the regulation of immune infiltrates and had predictive value for prognosis in LUAD.

Junctional Adhesion Molecule-Like Protein (JAML) Is Correlated with Prognosis and Immune Infiltrates in Lung Adenocarcinoma.

BackgroundJunctional adhesion molecule-like protein (JAML) is a member of the junctional adhesion molecule family and mediates migration of immune cells, but its function in cancers remains unclear. This study aimed to evaluate the role of JAML in the prognosis and immune infiltrates of lung adenocarcinoma (LUAD).Material/MethodsJAML expressions in LUAD tissues and normal tissues were compared using The Cancer Genome Atlas (TCGA) database and datasets from the Gene Expression Omnibus (GEO) database. The influence of JAML expression on prognosis was analyzed by Kaplan-Meier curve and Cox regression model. Interactive and functional analyses of JAML were performed by LinkedOmics and GeneMANIA databases. TIMER2.0, TISIDB, and GEPIA2 databases were used to investigate the correlation between JAML expression and immune infiltrates.ResultsJAML expression was decreased in LUAD (P<0.001), and lower JAML expression was associated with worse outcomes of LUAD patients. High JAML expression was the protective factor for overall survival (OS) (HR 0.706, 95% CI 0.500–0.997, P=0.048). Interactive and functional analyses suggested that co-expressed genes with JAML have an obvious link to immune-related pathways. In addition, JAML expression was positively associated with infiltrating levels of CD8+ T cells, CD4+ T cells, B cells, dendritic cells, macrophages, and neutrophils, and had significant correlations with diverse immune marker sets in LUAD.ConclusionsJAML expression was significantly correlated with prognosis and immune infiltrates. These preliminary findings suggested JAML could be considered as a potential prognostic biomarker and therapeutic target for LUAD.

SNX20AR/MiRNA-301a-3p/SNX20 Axis Associated With Cell Proliferation and Immune Infiltration in Lung Adenocarcinoma.

Lung cancer is the most common tumor with severe morbidity and high mortality. Increasing evidence has demonstrated that SNX20 plays crucial roles in the progression of human cancer. However, the functions and mechanism of SNX20 in LUAD are still barely known. Here, we employ the TCGA, GEO and CCLE databases to examine the expression of SNX20 in human varies cancer, the results shown that SNX20 is down-regulated in lung Adenocarcinoma, SNX20 level was significantly positive correlated with poor prognosis and lung cancer immune cell infiltration. We found that over-expression of SNX20 significantly restrain NSCLC cell proliferation and migration. Subsequently, we discover a network regulating SNX20 in LUAD, further study found that the decreased of the SNX20 likely caused by DNA hypermethylation. Furthermore, we identified that SNX20AR/miRNA-301a-3p mediated decreased of SNX20 correlated with lung cancer progression and cancer immune infiltration in LUAD. Our findings suggested that ncRNAs play a crucial role in the regulatory network of SNX20. Collectively, our findings demonstrate the suppressor roles of the SNX20AR/miRNA-301a-3p/SNX20 axis in Lung Adenocarcinoma, represent that SNX20 have the potential of as an effective therapeutic target in future.

DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma

BackgroundDihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored.MethodsHerein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan–Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated.ResultsIn this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan–Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2.ConclusionsIn summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target.HighlightsExpression of DPYSL2 was considerably lower in LUAD than in normal tissues.Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD.DPYSL2 can independently predict the LUAD outcomes.Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.

Integrated bioinformatics analysis reveals correlations of high TRIM59 expression with worse prognosis and immune infiltrates in lung adenocarcinoma

Abstract Objective: Most patients with advanced lung cancer have a poor prognosis. Recent studies have identified TRIM59 as a novel molecule that serves as a prognostic factor for the progression of non-small cell lung cancer. In the present study, we investigated the role of TRIM59 in predicting the prognosis of lung adenocarcinoma (LUAD) as well as the correlation between TRIM59 expression and immune infiltrates. Methods: We analyzed TRIM59 expression in normal and tumor tissues based on RNA-sequencing datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Forty-seven cases of LUAD tissues and their matching adjacent tissues were collected, and TRIM59 expression in tissue samples was demonstrated by immunohistochemistry. All tissue specimens were obtained under the approval of the Medical Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (approval No. IR2019001101; approved on April 3, 2019). The immune cell scores were calculated using the CIBERSORT database. The Tumor Immune Estimation Resource database was used to analyze the correlation between TRIM59 and immune cell activities. Results: TRIM59 was up-regulated in most cancer types. High TRIM59 expression predicted a worse prognosis in patients with LUAD (overall survival, P = 0.00096; disease-specific survival, P = 0.00056; disease-free interval, P = 0.0009; progression-free interval, P = 0.0012). Moreover, TRIM59 was highly expressed in patients with LUAD who had a poorer prognosis. TRIM59 also showed a significant correlation with the ESTIMATE score (P = 0.04) and stromal score (P = 0.005) in patients with LUAD. Notably, a significant correlation between TRIM59 and the tumor mutation burden was found in LUAD but in no other cancer types (P &lt; 0.001). Further investigation showed that TRIM59 had a significant correlation with gene markers on neutrophils and dendritic cells. Conclusion: TRIM59 is a potential prognosticator in LUAD and may be correlated with immune cell identification, immune cell infiltration, and immunotherapy checkpoints in LUAD.

A special prognostic indicator: tumor mutation burden combined with immune infiltrates in lung adenocarcinoma with TP53 mutation.

BackgroundTP53 mutation (TP53mut) is significantly associated with immunotherapy response in lung adenocarcinoma (LUAD), but not an ideal independent prognostic predictor for it. Here, we investigated a novel potential biomarker and constructed a model for prognostic prediction in LUAD TP53mut patients.Methods469 LUAD samples retrieved from The Cancer Genome Atlas database were divided into TP53wt (wild-type TP53) and TP53mut groups. TMB values were calculated based on the number of variants/exon lengths, and high- and low-TMB groups were divided by the median value. Differentially expressed genes (DEGs) between the two TMB groups were identified using “limma” package, and functional analyses were performed by Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis. The infiltration ratio of 22 immune cells were calculated with the CIBERSORT algorithm. Survival analyses were estimated by Kaplan-Meier with the log-rank test. Finally a TMB prognostic index (TMBPI) with receiver operating characteristic (ROC) curve was constructed and calculated to evaluate the predictive value in TP53mut LUAD.ResultsThere were diverse mutation types in 100% of TP53 mutants, while mutations were present in 86.5% of cases with TP53wt. TP53mut patients had higher TMB levels than TP53wt patients. Overall survival in TP53mut patients with low-TMB levels was significantly shorter than that in high-TMB TP53mut patients. High-TMB patients had higher levels of CD8 T cell and effector B cell, while lower levels of resting memory CD4 T cells, monocytes, activated dendritic cells, etc. than low-TMB patients. Poor survival outcome in TP53mut patients was correlated with lower effector B cell infiltration and higher activated dendritic cell. Survival risk analyses of 121 DEGs showed that good survival outcomes correlated positively with FBXO36 and KLHL35 expression levels, but correlated negatively with that of LINC0054. TMBPI analysis of the TP53mut patients showed that high-TMBPI patients had worse survival outcomes than low-TMBPI patients.ConclusionsOur findings suggest that the TMB value with immune infiltrates is a novel potential biomarker for prognostic prediction of TP53mut patients. The TMBPI combined with detection of TP53 mutation can be used as a better predictor of prognosis in LUAD.

Overexpression of BCCIP predicts an unfavorable prognosis and promotes the proliferation and migration of lung adenocarcinoma.

BackgroundLung cancer accounts for the highest rate of cancer‐related diagnosis and mortality. Lung adenocarcinoma (LUAD) is the most common histopathological type. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein. In different cancers, BCCIP plays different roles. The role of BCCIP in LUAD is still unknown.MethodsThe expression and prognostic value of BCCIP was analyzed using public databases, including LCE, GEPIA, TCGA, and clinical specimens. Bioinformatic analysis and vitro experiments were conducted to explore the biological functions of BCCIP in LUAD. By using the GEPIA and TIMER databases, we investigated the correlations between LUAD expression and immune infiltration in LUAD.ResultsCompared with normal tissue, LUAD tissue had a higher expression level of BCCIP and high expression level of BCCIP was detrimental to LUAD patient survival. The suppression of BCCIP inhibited LUAD cell proliferation, migration and resulted in G1/S phase arrest in vitro. Bioinformatic analysis demonstrated that BCCIP could be associated with cell cycle, DNA repair and E2F transcription factor family. There were significant correlations between BCCIP expression and immune infiltrates, including B cell, CD4+ T cell, macrophage, neutrophil and dendritic cells. Furthermore, BCCIP expression showed strong correlations with diverse immune marker sets in LUAD, such as B cell, macrophage and DC.ConclusionsOverexpression of BCCIP predicts an unfavorable prognosis and promotes the proliferation and migration of lung adenocarcinoma cells. BCCIP is correlated with immune infiltration in LUAD. Suppression of BCCIP may be a potential approach in the prevention and treatment of LUAD.

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis.

BackgroundOverexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).MethodsTCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.ResultsNPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (HNRNPC) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).ConclusionNPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

High expression of PIMREG predicts poor survival outcomes and is correlated with immune infiltrates in lung adenocarcinoma

BackgroundPIMREG is upregulated in multiple cancer types. However, the potential role of PIMREG in lung adenocarcinoma (LUAD) remains unclear. The present study aimed to explore its clinical significance in LUAD.MethodsUsing the Cancer Genome Atlas (TCGA) databases, we obtained 513 samples of LUAD and 59 normal samples from the Cancer Genome Atlas (TCGA) databases to analyze the relationship between PIMREG and LUAD. We used t and Chi-square tests to evaluate the level of expression of PIMREG and its clinical implication in LUAD. The prognostic value of PIMREG in LUAD was identified through the Kaplan–Meier method, Cox regression analysis, and nomogram. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were performed to screen biological pathways and analyze the correlation of the immune infiltrating level with the expression of PIMREG in LUAD.ResultsPIMREG was highly expressed in patients with LUAD. Specifically, the level of PIMREG gradually increased from pathological stage I to IV. Further, we validated the higher expression of PIMREG expressed in LUAD cell lines. Moreover, PIMREG had a high diagnostic value, with an -AUC of 0.955. Kaplan–Meier survival and Cox regression analyses revealed that the high expression of PIMREG was independently associated with poor clinical outcomes. In our prognostic nomogram, the expression of PIMREG implied a significant prognostic value. Gene set enrichment analysis (GSEA) identified that the high expression PIMREG phenotype was involved in the mitotic cell cycle, mRNA splicing, DNA repair, Rho GTPase signaling, TP53 transcriptional regulation, and translation pathways. Next, we also explored the correlation of PIMREG and tumor-immune interactions and found a negative correlation between PIMREG and the immune infiltrating level of T cells, macrophages, B cells, dendritic cells (DCs) , and CD8+ T cells in LUAD.ConclusionsHigh levels of PIMREG correlated with poor prognosis and immune infiltrates in LUAD.

Upregulation of LIMK1 Is Correlated With Poor Prognosis and Immune Infiltrates in Lung Adenocarcinoma.

BackgroundProtein-coding gene LIM Domain Kinase 1 (LIMK1) is upregulated in various tumors and reported to promote tumor invasion and metastasis. However, the prognostic values of LIMK1 and correlation with immune infiltrates in lung adenocarcinoma are still not understood. Therefore, we evaluated the prognostic role of LIMK1 and its correlation with immune infiltrates in lung adenocarcinoma.MethodsTranscriptional expression profiles of LIMK1 between lung adenocarcinoma tissues and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). The LIMK1 protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas. Receiver operating characteristic (ROC) curve was used to differentiate lung adenocarcinoma from adjacent normal tissues. Kaplan-Meier method was conducted to assess the effect of LIMK1 on survival. Protein-protein interaction (PPI) networks were constructed by the STRING. Functional enrichment analyses were performed using the “ClusterProfiler” package. The relationship between LIMK1 mRNA expression and immune infiltrates was determined by tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB).ResultsThe expression of LIMK1 in lung adenocarcinoma tissues was significantly upregulated than those in adjacent normal tissues. Increased LIMK1 mRNA expression was associated with lymph node metastases and high TNM stage. The ROC curve analysis showed that with a cutoff level of 4.908, the accuracy, sensitivity, and specificity for LIMK1 differentiate lung adenocarcinoma from adjacent controls were 69.5, 93.2, and 71.9%, respectively. Kaplan-Meier survival analysis showed lung adenocarcinoma patients with high- LIMK1 had a worse prognosis than those with low- LIMK1 (43.1 vs. 55.1 months, P = 0.028). Correlation analysis indicated LIMK1 mRNA expression was correlated with tumor purity and immune infiltrates.ConclusionUpregulated LIMK1 is significantly correlated with poor survival and immune infiltrates in lung adenocarcinoma. Our study suggests that LIMK1 can be used as a biomarker of poor prognosis and potential immune therapy target in lung adenocarcinoma.

Comprehensive analysis of competitive endogenous RNA associated with immune infiltration in lung adenocarcinoma

To identify the prognostic biomarker of the competitive endogenous RNA (ceRNA) and explore the tumor infiltrating immune cells (TIICs) which might be the potential prognostic factors in lung adenocarcinoma. In addition, we also try to explain the crosstalk between the ceRNA and TIICs to explore the molecular mechanisms involved in lung adenocarcinoma. The transcriptome data of lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database, and the hypergeometric correlation of the differently expressed miRNA-lncRNA and miRNA-mRNA were analyzed based on the starBase. In addition, the Kaplan–Meier survival and Cox regression model analysis were used to identify the prognostic ceRNA network and TIICs. Correlation analysis was performed to analysis the correlation between the ceRNA network and TIICs. In the differently expressed RNAs between tumor and normal tissue, a total of 190 miRNAs, 224 lncRNAs and 3024 mRNAs were detected, and the constructed ceRNA network contained 5 lncRNAs, 92 mRNAs and 10 miRNAs. Then, six prognostic RNAs (FKBP3, GPI, LOXL2, IL22RA1, GPR37, and has-miR-148a-3p) were viewed as the key members for constructing the prognostic prediction model in the ceRNA network, and three kinds of TIICs (Monocytes, Macrophages M1, activated mast cells) were identified to be significantly related with the prognosis in lung adenocarcinoma. Correlation analysis suggested that the FKBP3 was associated with Monocytes and Macrophages M1, and the GPI was obviously related with Monocytes and Macrophages M1. Besides, the LOXL2 was associated with Monocytes and Activated mast cells, and the IL22RA1 was significantly associated with Monocytes and Macrophages M1, while the GPR37 and Macrophages M1 was closely related. The constructed ceRNA network and identified Monocytes, Macrophages M1 and activated Mast cells are all prognostic factors for lung adenocarcinoma. Moreover, the crosstalk between the ceRNA network and TIICs might be a potential molecular mechanism involved.

Overexpression of LILRB2 (ILT4) is correlated with immunosuppressive immune infiltration in lung adenocarcinoma.

e20519 Background: Immune checkpoint inhibitors have revolutionized the patterns of tumor treatment with significantly improved survival. However, it’s worth noting that the objective response rate of PD-1/PD-L1 inhibitors monotherapy is just 20% in non-small cell lung cancer (NSCLC) patients, and biomarkers for the prognosis of patients receiving PD-1/PD-L1 inhibitors are urgently needed. LILRB2 (ILT4) is known as an immunosuppressive molecule and promotes the development and progression of NSCLC. However, the relationship between LILRB2 expression and immune microenvironment remains unclear in patients with lung adenocarcinoma. Methods: Expression profile and corresponding clinicopathological data of patients with lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database. TIMER 2.0 was used to investigate the relationship between LILRB2 expression and immune infiltrates, including T cell subset, macrophage and so on. Cox proportional hazard model was also performed to evaluate the role LILRB2 expression and immune infiltrations in prognostic prediction of patients with lung adenocarcinoma. Results: 515 patients with lung adenocarcinoma were included in analysis from TCGA dataset. LILRB2 expression was found to have significant negative correlation with CD8+ T cell infiltration (P = 0.0012), and positive correlation with CD4+ T cell infiltration (P &lt; 0.001). There were also significant positive correlations between LILRB2 expression and Treg (P = 0.0083), cancer associated fibroblast (P &lt; 0.001), monocyte (P &lt; 0.001), M2 macrophage (P &lt; 0.001) infiltration, which was regarded as the marker of immunosuppressive microenvironment. Notably, there were also significant association between the expression of LILRB2 and PD-1 (P &lt; 0.001) and PD-L1(P &lt; 0.001). In terms of survival analysis, high level of Treg (HR = 0.86, P = 0.03) and M2 macrophage (HR = 0.84, P = 0.017) infiltration was associated with poor prognosis of patients with lung adenocarcinoma. However, the level of CD8+T cell (HR = 0.93, P = 0.298), CD4+ T cell (HR = 0.933, P = 0.321), and LILRB2 expression (P = 0.56) was not associated with the survival of patient with lung adenocarcinoma. Conclusions: The overexpression of LILRB2 is significantly correlated with immunosuppressive immune infiltration and microenvironment in lung adenocarcinoma and might be the potential predictive biomarkers for the PD-1/PD-L1 inhibitors.

The low expression of NUP62CL indicates good prognosis and high level of immune infiltration in lung adenocarcinoma.

A primary factor in tumor morbidity and mortality, lung adenocarcinoma (LUAD) is known to be a major subtype of lung cancer, having the lowest survival rate among all other cancers. Using The Cancer Genome Atlas (TCGA) database the relationship between the immune infiltrate and the NUP62CL was explored and the value of the NUP62CL expression in the prognosis and diagnosis LUAD was examined. Using the logistic regression and the Wilcoxon signed‐rank test the relationship between the NUP62CL and the clinico‐pathological features was analyzed. There was a significant correlation between the clinical stage (p = 0.005), the N (p = 0.004), and the decreased expression of NUP62CL. The prognosis of LUAD with high NUP62CL expression was revealed to be worse than that with low NUP62CL expression (p < 0.001) by the Kaplan‐Meier survival analysis. The potentiality of NUP62CL to be a significant factor of prognosis for LUAD was indicated by the analyses of the multivariate and the univariate Cox regression models. In LUAD, the crucial role of recombination and maintenance of telomere as a significant pathway for NUP62CL was suggested by the Gene Set Enrichment Analysis (GSEA). To analyze the correlation between the genes and the tumor infiltrating immune cells the CIBERSORT was used. Moreover the positive correlation with the NUP62CL expression in LUAD of the infiltration level of the tumor infiltrating B lymphocytes and memory CD4+ T cells was exhibited by CIBERSORT. Therefore, NUP62CL may be a new valuable prognostic indicator for LUAD.

TYK2 is a prognostic biomarker and associated with immune infiltration in the lung adenocarcinoma microenvironment

Lung adenocarcinoma (LUAD) remains a major disease with high morbidity and mortality. The Janus kinases (JAKs) play a significant part in cellular biological process, inflammation and immunity. The role of JAK family in LUAD is still ambiguous. Various bioinformatics web portals were applied to explore the prognostic value of JAK family and their correlation with immune infiltration in LUAD. JAK1/2 was downregulated, whereas JAK3/TYK2 was upregulated in patients with LUAD compared with the healthy controls in subgroup analyses based on gender, age, smoking habits, cancer stage, TP53 mutation status, and nodal metastasis status. Drug sensitivity indicated that low expression of JAK3 and TYK2 were resistant to most of the small molecules or drugs. High TYK2 expression was associated with favorable overall survival and relapse free survival in LUAD. Moreover, univariate and multivariate analysis revealed that clinical stage, lymphatic node metastasis and TYK2 expression were the independent factors affecting the prognosis of LUAD patients. TYK2 expression in LUAD patients was positively associated with the abundance of immune cells (B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells) and immune biomarker sets. Moreover, TYK2 was mainly involved in RNA binding, transcriptional mis-regulation in cancer and cell cycles. We also identified several TYK2-associated miRNA or transcription factor targets in LUAD. Our results indicated that TYK2 was a biomarker and associated with prognosis and immune infiltration in LUAD, laying a foundation for further study about the role of TYK2 in the carcinogenesis and progression of LUAD.

Identification of SHMT2 as a Potential Prognostic Biomarker and Correlating with Immune Infiltrates in Lung Adenocarcinoma.

It has attracted growing attention that the role of serine hydroxy methyl transferase 2 (SHMT2) in various types of cancers. However, the prognostic role of SHMT2 in lung adenocarcinoma (LUAD) and its relationship with immune cell infiltration is not clear. In this study, the information of mRNA expression and clinic data in LUAD were, respectively, downloaded from the GEO and TCGA database. We conducted a biological analysis to select the signature gene SHMT2. Online databases including Oncomine, GEPIA, TISIDB, TIMER, and HPA were applied to analyze the characterization of SHMT2 expression, prognosis, and the correlation with immune infiltration in LUAD. The mRNA expression and protein expression of SHMT2 in LUAD tissues were higher than in normal tissue. A Kaplan-Meier analysis showed that patients with lower expression level of SHMT2 had a better overall survival rate. Multivariate analysis and the Cox proportional hazard regression model revealed that SHMT2 expression was an independent prognostic factor in patients with LUAD. Meanwhile, the gene SHMT2 was highly associated with tumor-infiltrating lymphocytes in LUAD. These results suggest that the SHMT2 gene is a promising candidate as a potential prognostic biomarker and highly associated with different types of immune cell infiltration in LUAD.

Seven interferon gamma response genes serve as a prognostic risk signature that correlates with immune infiltration in lung adenocarcinoma.

Interferon-gamma (IFN-γ) plays a complex role in modulating tumor microenvironment during lung adenocarcinoma (LUAD) development. In order to define the role of IFN-γ response genes in LUAD progression, we characterized the gene expression, mutation profile, protein-protein interaction of 24 IFN-γ response genes, which exhibited significant hazard ratio in overall survival. Two subgroups of LUAD from the TCGA cohort, which showed significant difference in the survival rate, were identified based on the expression of these genes. Furthermore, LASSO penalized cox regression model was used to derive a risk signature comprising seven IFN-γ response genes, including CD74, CSF2RB, PTPN6, MT2A, NMI, LATS2, and PFKP, which can serve as an independent prognostic predictor of LUAD. The risk signature was validated in an independent LUAD cohort. The high risk group is enriched with genes regulating cell cycle and DNA replication, as well as a high level of pro-tumor immune cells. In addition, the risk score is negatively correlated with the expression of immune metagenes, but positively correlated with DNA damage repair genes. Our findings reveal that seven-gene risk signature can be a valuable prognostic predictor for LUAD, and they are crucial participants in tumor microenvironment of LUAD.