Study On The Prognostic Model Of Immune-related Genes In Lung Adenocarcinoma And Its Correlation With Immunotherapy

Background and Aim: Lung cancer is one of the common primary malignancies,and adenocarcinoma(LUAD)has become the most common subtype of lung cancer with an increasing trend in incidence.A large number of immune-related genes have now been found to be associated with lung adenocarcinoma development and prognosis.In this study,we analyzed immune genes related to lung adenocarcinoma based on The Cancer Genome Atlas(TCGA)database and GEO database,and conducted immune gene prognostic model construction and immune correlation studies to explore the influence of immune-related genes on the development process and prognosis of lung adenocarcinoma.METHODS: We obtained gene expression and clinical data of a total of 999 lung adenocarcinoma patients from TCGA database and GEO database,and immune genes from ImmPort and InnateDB databases.Immune-related differential genes(IRGs)were obtained by intersecting the TCGA database with the immune gene database,and then constructing WGCNA co-expression networks,single-factor COX regression analysis and multi-factor COX regression analysis were performed to build prediction models for immune-related genes and calculate the risk coefficients.The median risk coefficient was used to divide them into high-risk and low-risk groups,and Kaplan-Meier(K-M)survival curves and receiver operating charateriatic(ROC)curves were plotted for the high-risk and low-risk groups,respectively,to assess the predictive value of the model in lung adenocarcinoma patients.The immunogenetic prognostic model we constructed was validated using the GEO database.The efficacy of immunotherapy in the high-risk and low-risk groups was analyzed by TIDE score and compared with the TIDE model and TIS model for superiority.We also performed GSEA enrichment analysis to analyze the role of the two groups in biological functions and pathways.We analyzed the immune cell infiltration in both groups and performed the relationship analysis between immune-related genes and immune cell abundance in the c Bioportal database.To further explore whether the expression of immune-related genes differed between lung adenocarcinoma and normal lung tissue,we chose the Kaplan Meier mapper online tool for the analysis.Finally,we performed genetic alteration profile,expression profile and correlation analysis of IRGs in the GEPIA database.Results:1.679 IRGs that met the screening criteria(P value < 0.05 and |log2FC > 1|)were obtained based on the TCGA database,including 254 up-regulated genes and 425down-regulated genes.2.5 prognosis-related IRGs(CAT,FGF2,GJA1,IL7 R and SHC3)were obtained by constructing WGCNA co-expression network,one-way COX regression analysis and multi-way COX regression analysis.3.Immune-related gene prognostic models for lung adenocarcinoma were constructed and evaluated.K-M survival curves showed that patients in the high-risk group had shorter survival and worse prognosis(P < 0.05),with the area under the ROC curve(AUC)of 0.695,0.628 and 0.610 at 1,2 and 3 years,respectively;the K-M survival curves at external validation(P < 0.05)were the same as the results of the validation cohort.4.GSEA enrichment analysis showed that the high-risk group was significantly enriched in cell cycle,DNA replication,mismatch repair,P53 signaling pathway,and SLE signaling pathways in the KEGG pathway,while the low-risk group was significantly enriched in allograft rejection,asthma,hematopoietic cell lineage,intestinal immune network generated by IGA,and Leishmania protozoa infection process;in GO enrichment In the GO enrichment analysis,the high-risk group was mainly enriched in biological processes such as chromatin assembly or disassembly,regulation of chromatin organization involved in translation,keratinization,DNA conformational changes,and DNA packaging,while the low-risk group was mainly enriched in biological processes such as regulation of immune effector processes,regulation of leukocyte-mediated immunity,endocytic vesicles,type Ⅱ MHC protein complexes,and T-cell receptor complexes.5.The TIDE score showed a higher benefit of immunotherapy in the high-risk group,and the prognostic model we constructed was superior to the TIDE and TIS models.6.There were differences in plasma cells,monocytes,dormant CD4 memory T cells,active CD4 memory T cells,M0-type macrophages,M2-type macrophages,dormant dendritic cells and dormant mast cells in the high-and low-risk groups,with dormant CD4 memory T cells,monocytes,M2-type macrophages,dormant dendritic cells and dormant mast cells being highly infiltrated in the high-risk group,while plasma cells The high infiltration of plasma cells,activated CD4 memory T cells and M0 macrophages was observed in the low risk group.7.The expression of CAT,FGF2,GJA1,IL7 R and SHC3 correlated with immune purity and six types of infiltrating immune cells in the immune microenvironment of lung adenocarcinoma.Analysis of the independent effects of the five genes on lung adenocarcinoma prognosis revealed that they were all independent risk factors for lung adenocarcinoma prognosis.five IRGs had varying degrees of genetic alteration in lung adenocarcinoma samples.In addition,CAT,FGF2,GJA1,IL7 R and SHC3 were down-regulated in lung adenocarcinoma tissues and the expression of the five genes interacted and influenced each other.Conclusions and implications:1.In this study,the prognostic model of CAT,FGF2,GJA1,IL7 R and SHC3immunogene-related prognosis of lung adenocarcinoma constructed based on the TCGA database can effectively predict the prognosis of lung adenocarcinoma patients and can assess the efficacy of immunotherapy.2.We found that CAT,FGF2,GJA1,IL7 R and SHC3 immune-related genes were associated with the degree of immune cell infiltration in the immune microenvironment of lung adenocarcinoma,and that these five genes were differentially expressed in lung adenocarcinoma and normal tissues and the expression of the five genes influenced each other.five genes were independent risk factors for lung adenocarcinoma prognosis.Therefore,the immune-related gene prognostic model constructed in this study can effectively predict the prognosis of lung adenocarcinoma patients.CAT,FGF2,GJA1,IL7 R,and SHC3 may become biomarkers for immunotherapy of lung adenocarcinoma,which opens up new ideas for us to study immunotherapy of lung adenocarcinoma and infiltration of immune cells in the tumor microenvironment.