GDPLichi: a DNA Damage Repair-Related Gene Classifier for Predicting Lung Adenocarcinoma Immune Checkpoint Inhibitors Response.
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ABSTRACT:
SUBMITTER: Leng Y
PROVIDER: S-EPMC8713481 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTumour cells interfere with normal immune functions by affecting the expression of some immune-related genes, which play roles in the prognosis of cancer patients. In recent years, immunotherapy for tumours has been widely studied, but a practical prognostic model based on immune-related genes in lung adenocarcinoma comparable to existing model has not been established and reported.MethodsWe first obtained publicly accessible lung adenocarcinoma RNA expression data from The Cancer Genome Atlas (TCGA) for differential gene expression analysis and then filtered immune-related genes based on the ImmPort database. By using the lasso algorithm and multivariate Cox Proportional-Hazards (CoxPH) regression analysis, we identified candidate genes for model development and validation. The robustness of the model was further examined by comparing the model with three established gene models.ResultsGene expression data from a total of 524 lung adenocarcinoma patients from TCGA were used for model development. We identified four biomarkers (MAP3K8, CCL20, VEGFC, and ANGPTL4) that could predict overall survival in lung adenocarcinoma (HR = 1.98, 95% CI 1.48 to 2.64, P = 4.19e-06) and this model could be used as a classifier for the evaluation of low-risk and high-risk groups. This model was validated with independent microarray data and was highly comparable with previously reported gene expression signatures for lung adenocarcinoma prognosis.ConclusionsIn this study, we identified a practical and robust four-gene prognostic model based on an immune gene dataset with cross-platform compatibility. This model has potential value in improving TNM staging for survival predictions in patients with lung adenocarcinoma.ImpactThe study provides a method of immune relevant gene prognosis model and the identification of immune gene classifier for the prediction of lung adenocarcinoma prognosis with RNA sequencing and microarray compatibility.
| S-EPMC7001261 | biostudies-literature
Project description:Background:Immune checkpoint inhibitors (ICIs) are an important treatment modality that must be considered for patients with lung adenocarcinoma (LUAD). However, ICIs are effective only in some of these patients. Therefore, identifying biomarkers that accurately predict the prognosis of patients with LUAD treated with ICIs can help maximize their therapeutic benefits. This study aimed to identify a new potential predictor to better select and optimally benefit LUAD patients. Methods:We first collected and analyzed a discovery immunotherapy cohort comprising clinical and mutation data for LUAD patients. Then, we evaluated whether the specific mutated genes can act as predictive biomarkers in this discovery immunotherapy cohort and further validated the findings in The Cancer Genome Atlas (TCGA) project LUAD cohort. Gene set enrichment analysis (GSEA) was used to explore possible alterations in DNA damage response (DDR) pathways within the gene mutation. Moreover, we analyzed whole-exome sequencing (WES) and drug sensitivity response data for LUAD cell lines in the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results:Among the mutated genes screened from both the ICI treatment and TCGA-LUAD cohorts, NTRK3 mutation (mutant-type NTRK3, NTRK3-MT) was strongly associated with immunotherapy. First, significant differences in overall survival (OS) were observed between patients with NTRK3-MT and those with NTRK3-WT in the ICI treatment cohort but not in the non-ICI-treated TCGA-LUAD cohort. We then analyzed the association of NTRK3-MT with clinical characteristics and found the tumor mutation burden (TMB) to be significantly higher in both NTRK3-MT cohorts. However, significant differences in neoantigen levels and smoking history were found only for NTRK3-MT in the LUAD cohort from TCGA. Furthermore, some immune-related genes and immune cell-related genes were significantly upregulated in patients with NTRK3-MT compared to those with NTRK3-WT. In addition, NTRK3 mutation affected the deregulation of some signaling pathways and the DDR pathway. Conclusions:Our findings suggest that NTRK3-MT can predict the prognosis of patients with LUAD treated by ICIs and that it may have clinical significance for immunotherapy.
| S-EPMC7434857 | biostudies-literature
Project description:BackgroundAlthough TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported.MethodsAn integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway.FindingsThe TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy.InterpretationOur study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs.FundingThe study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).
| S-EPMC7494676 | biostudies-literature
Project description:Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are increasingly used in combination with cytotoxic treatments, such as chemotherapy. Although combined treatments are more effective, not all patients respond to the therapy; therefore, a detailed understanding of the effect of treatment combinations at the tumour level is needed. The present study aimed to explore whether ICIs could affect the cytotoxic effects of chemotherapy on lung adenocarcinoma cell lines with different PD-L1 expression levels (high, HCC-44; low, A-549). Using the resazurin-based assay, the efficacy of seven chemotherapeutic agents (cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel and paclitaxel) was compared in the presence or absence of the individually chosen single doses of four ICIs (nivolumab, pembrolizumab, atezolizumab and durvalumab). The results revealed that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or lung adenocarcinoma cell line used. Durvalumab was the most promising ICI, which potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. By contrast, nivolumab, exhibited depotentiating trends in several combinations. The immunostaining of γH2AX in treated cells confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage; however, this effect was strongly dependent on the chemotherapy agent and cell line used. Our future studies aim to address the specific mechanisms underlying the observed ICI-induced potentiation or depotentiation.
| S-EPMC10018276 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) are novel immunotherapy-based drugs that have become increasingly popular in the treatment of lung cancer. Researchers have recognized ocular immune-related adverse events (irAEs) secondary to ICIs because of their vision-threatening characteristics. However, they are incompletely characterized and no studies have reported the ICI-related ocular irAEs in lung cancer. Therefore, we aimed to comprehensively illustrate the clinical characteristics, contributory factors, diagnosis, and management of ICI-related ocular irAEs in lung cancer, based on previously reported 79 patients. Ophthalmoplegia (40.51%), uveitis (20.25%), and dry eye (17.72%) were the most common ICI-related ocular irAEs in lung cancer. Ptosis was the most common (36.71%) and the highest mortality (23.33%) of ophthalmoplegia. Patients in Asia and patients who underwent combination therapy with programmed cell death-1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors demonstrated significantly higher frequency of ophthalmoplegia than other ocular irAEs. Most ICI-related ophthalmoplegia and uveitis in lung cancer were observed in the first 10 weeks following the initiation of ICIs. Furthermore, the onset time of dry eye and other ocular irAEs was much longer. In addition, 92.31% of the patients with ocular irAEs other than ophthalmoplegia could be remised. In conclusion, ocular irAEs secondary to ICIs in lung cancer are non-negligible, particularly ophthalmoplegia. Ethnicity and the type of ICIs play important roles in the distribution of ocular irAEs. ICI-related ophthalmoplegia in lung cancer presented with early onset and worse prognosis features, thus necessitating further attention.
| S-EPMC8421677 | biostudies-literature
Project description:Background: Lung cancer has always been the most prevalent cancer. Lung adenocarcinoma (LUAD) is the most common lung cancer subtype and has a high tumor mutation rate. In addition to KRAS, EGFR, ALK, HER2, ROS1, and BRAF, which are known to have high mutation rates, we discovered some new mutated genes, such as catenin alpha-2 (CTNNA2), in LUAD patients treated with immune checkpoint inhibitors (ICIs). These mutant genes are potential therapeutic targets for LUAD. Methods: We analyzed a cohort of LUAD patients with somatic mutation and survival data in the Cancer Genome Atlas (TCGA) database and a cohort of LUAD patients receiving immune checkpoint inhibitors with clinical data and whole-exome sequencing (WES) mutation data to evaluate the role of CTNNA2 gene mutation in LUAD. In addition, CIBERSORT was used to analyze the immune characteristics of CTNNA2 wild-type patients and CTNNA2 mutant-type patients, and gene set enrichment analysis (GSEA) was employed for pathway enrichment analysis. The results were verified by downloading data regarding the drug sensitivity of LUAD cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results: We found that CTNNA2 mutation was associated with longer overall survival (OS) in LUAD patients. Analysis of the cohort from the Cancer Genome Atlas showed that patients with CTNNA2 mutation had more tumor neoantigens and a greater tumor mutation burden (TMB). Through further analysis of the tumor immune microenvironment, we found that in LUAD patients with CTNNA2 mutations, the gene expression levels of chemokine C-X-C motif chemokine 9 (CXCL9) and granzyme B (GZMB) were elevated, and the gene expression level of inhibitory receptor killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) was significantly reduced. These alterations might affect gene expression in macrophages, NK cells, and mast cell markers. In addition, LUAD patients with CTNNA2 mutation had a significantly increased number of mutations in DNA damage response (DDR) genes. The drug susceptibility results and gene set enrichment analysis showed that after CTNNA2 mutation occurred, changes were found in the DNA damage response pathway, the phosphoinositide 3-kinase (PI3K) pathway and others, indicating that CTNNA2 mutation can regulate the activation of PI3K and DDR pathways. Conclusion: Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future.
| S-EPMC8215613 | biostudies-literature
Project description:AimsLung adenocarcinoma (LUAD) cells could escape from the monitoring of immune cells and metastasize rapidly through immune escape. Therefore, we aimed to develop a method to predict the prognosis of LUAD patients based on immune checkpoints and their associated genes, thus providing guidance for LUAD treatment.MethodsGene sequencing data were downloaded from the Cancer Genome Atlas (TCGA) and analyzed by R software and R Bioconductor software package. Based on immune checkpoint genes, kmdist clustering in ConsensusClusterPlus R software package was utilized to classify LUAD. CIBERSORT was used to quantify the abundance of immune cells in LUAD samples. LM22 signature was performed to distinguish 22 phenotypes of human infiltrating immune cells. Gene set variation analysis (GSVA) was performed on immune checkpoint cluster and immune checkpoint score using GSVA R software package. The risk score was calculated by LASSO regression coefficient. Gene Ontology (GO), Hallmark, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. PROC was performed to generate the ROC curve and calculate the area under the curve (AUC).ResultsAccording to the immune checkpoint, LUAD was classified into clusters 1 and 2. Survival rate, immune infiltration patterns, TMB, and immune score were significantly different between the two clusters. Functional prediction showed that the functions of cluster 1 focused on apoptosis, JAK/STAT signaling pathway, TNF-α/NFκB signaling pathway, and STAT5 signaling pathway. The risk score model was constructed based on nine genes associated with immune checkpoints. Survival analysis and ROC analysis showed that patients with high-risk score had poor prognosis. The risk score was significantly correlated with cancer status (with tumor), male proportion, status, tobacco intake, and cancer stage. With the increase of the risk score, the enrichment of 22 biological functions increased, such as p53 signaling pathway. The signature was verified in IMvigor immunotherapy dataset with excellent diagnostic accuracy.ConclusionWe established a nine-gene signature based on immune checkpoints, which may contribute to the diagnosis, prognosis, and clinical treatment of LUAD.
| S-EPMC8337117 | biostudies-literature
Project description:Background: In lung adenocarcinoma (LUAD), the predictive role of immune-related subgroup classification in immune checkpoint blockade (ICB) therapy remains largely incomplete. Methods: Transcriptomics analysis was performed to evaluate the association between immune landscape and ICB therapy in lung adenocarcinoma and the associated underlying mechanism. First, the least absolute shrinkage and selection operator (LASSO) algorithm and K-means algorithm were used to identify immune related subgroups for LUAD cohort from the Cancer Genome Atlas (TCGA) database (n = 572). Second, the immune associated signatures of the identified subgroups were characterized by evaluating the status of immune checkpoint associated genes and the immune cell infiltration. Then, potential responses to ICB therapy based on the aforementioned immune related subgroup classification were evaluated via tumor immune dysfunction and exclusion (TIDE) algorithm analysis, and survival analysis and further Cox proportional hazards regression analysis were also performed for LUAD. In the end, gene set enrichment analysis (GSEA) was performed to explore the metabolic mechanism potentially responsible for immune related subgroup clustering. Additionally, two LUAD cohorts from the Gene Expression Omnibus (GEO) database were used as validation cohort. Results: A total of three immune related subgroups with different immune-associated signatures were identified for LUAD. Among them, subgroup 1 with higher infiltration scores for effector immune cells and immune checkpoint associated genes exhibited a potential response to IBC therapy and a better survival, whereas subgroup 3 with lower scores for immune checkpoint associated genes but higher infiltration scores for suppressive immune cells tended to be insensitive to ICB therapy and have an unfavorable prognosis. GSEA revealed that the status of glucometabolic reprogramming in LUAD was potentially responsible for the immune-related subgroup classification. Conclusion: In summary, immune related subgroup clustering based on distinct immune associated signatures will enable us to screen potentially responsive LUAD patients for ICB therapy before treatment, and the discovery of metabolism associated mechanism is beneficial to comprehensive therapeutic strategies making involving ICB therapy in combination with metabolism intervention for LUAD.
| S-EPMC8554034 | biostudies-literature
Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs) have dramatically revolutionized lung cancer treatment, providing unprecedented clinical benefits. However, immune-related pneumonitis (IRP) caused by ICIs has aroused widespread concern due to its high rate of discontinuation and mortality. This network meta-analysis (NMA) aims to compare the risks of IRP among different regimens for advanced lung cancer. METHODS:Phase II and III randomized clinical trials (RCTs) were searched from electronic databases. The rates of grade 1-5 IRP and grade 3-5 IRP were systematically extracted. An NMA was conducted among chemotherapy, ICIs monotherapy, dual ICIs combination, and ICIs+chemotherapy. Subgroup analysis was also compared based on specific types of ICIs. RESULTS:Twenty-five RCTs involving 17,310 patients were eligible for inclusion. Compared with chemotherapy, ICI-based regimens were associated with an increased risk of grade 1-5 IRP and grade 3-5 IRP. Compared with ICIs+chemotherapy, ICIs monotherapy (grade 1-5: OR 2.14, 95% credible interval 1.12 to 4.80; grade 3-5: 3.03, 1.491 to 6.69) and dual ICIs combination (grade 1-5: 3.86, 1.69 to 9.89; grade 3-5: 5.12, 2.01 to 13.68) were associated with a higher risk of grade 1-5 IRP and grade 3-5 IRP. No significant difference was found between dual ICIs combination and ICIs monotherapy in grade 1-5 IRP (1.85, 0.91 to 3.37) or in grade 3-5 IRP (1.65, 0.81 to 3.37). Besides, compared with programmed cell death protein 1 (PD-1) inhibitors (2.56, 1.12 to 6.60), a lower risk of grade 1-5 IRP was observed in programmed cell death ligand 1 (PD-L1) inhibitors. CONCLUSION:Compared with chemotherapy, using ICIs is associated with an increased risk of IRP. ICIs+chemotherapy is associated with a lower risk of IRP compared with dual ICIs combination and ICIs monotherapy. PD-1 inhibitors are associated with a higher risk of 1-5 grade IRP compared with PD-L1 inhibitors.
| S-EPMC7462235 | biostudies-literature
Project description:Lung cancer is predominantly a disease of the elderly with about 50% of diagnoses in patients aged ?70 years and about 14% in those older than 80. Medical and physiological characteristics of elderly cancer patients make the choice of their better treatment more challenging. Furthermore, aging is accompanied by the so called "immunosenescence" phenomenon, the age-related decline in the immune system that is one of the potential reasons of increase of the incidence and prevalence of most cancers. There is a growing interest in understanding of immunosenescence and how it may correlate with the use of immune checkpoint inhibitors in elderly non-small cell lung cancer (NSCLC) patients. The survival benefit achieved by immunotherapy in all histologies and therapy line settings, added to its manageable toxicity profile, has dramatically changed the scenario of advanced NSCLC treatment. At subgroup analyses of randomized clinical trials, elderly NSCLC population seems to benefit from anti-programmed death-1 (anti-PD-1)/anti-programmed death ligand-1 (anti-PD-L1) agents' treatment. These efficacy data were also confirmed by studies in real-life setting. The key-points of aging and immunosenescence are described, focusing on the role of immune checkpoint inhibitors in elderly NSCLC population.
| S-EPMC5994497 | biostudies-literature