Establishment Of Tumor Microenvironment Assessment Oriented Precise Immunotherapy Decision System For Gastric Cancer And Its Clinical Application

Checkpoint immunotherapy has revolutionized the treatment of advanced gastric cancer,but only a few patients can benefit from the treatment.To find molecular biomarkers that can predict the treatment efficacy is a critical clinical step for researchers.At the same time,with the rise of immunotherapy,the research value of tumor microenvironment has become increasingly prominent.Using a large number of samples,bioinformatics data and computer algorithms,our previous studies have found that tumor microenvironment is significantly related to the prognosis and treatment response of gastric cancer patients.Therefore,the purpose of this study is:(1)to identify the tumor microenvironment subtypes of gastric cancer patients based on the characteristics of the tumor microenvironment;(2)to establish tumor microenvironment score based on tumor microenvironment classification;(3)to reduce the dimension of tumor microenvironment genes and use NanoString technology for clinical verification;(4)to mine tumor microenvironment relevant biomarkers based on tumor microenvironment score from multi-omics data.The main results are as follows1.Identifying the characteristics of cell infiltration pattern in tumor microenvironment of gastric cancer.Based on the transcriptomic data of GEO and TCGA,the tumor microenvironment cell infiltration status of gastric cancer was evaluated by deconvolution algorithm.Three robust tumor microenvironment subtypes(TMEculsterA,TMEculsterB,TMEculsterC)were found in gastric cancer patients by unsupervised clustering and consensus clustering algorithm.There were significant differences in phenotype,molecular biology,and survival among the three subtypes.2.Based on the characteristics of tumor microenvironment classification,a quantitative tumor microenvironment classification score was established.On the basis of tumor microenvironment classification,the characteristic genes representing each type were identified by differentially express gene analysis and machine learning algorithm,and the tumor microenvironment score(TMEscore)was calculated by the PCA algorithm.The tumor microenvironment score has a significant prognostic value which was validated in multiple gastric cancer cohorts,and the immunotherapy clinical trial data of gastric cancer and other tumors have confirmed the accuracy of the score in immunotherapy prediction.3.Dimension reduction of tumor microenvironment characteristic genes,design of NanoString kit,and clinical verification of the predictive value in multi-center gastric cancer cohorts treated with immunotherapy.On the basis of the above research,in order to achieve better clinical transformation,we screened the gene set related to tumor microenvironment score and designed the NanoString kit.The data from several hospitals verified the predictive value of the score in immunotherapy.4.Based on the tumor microenvironment evaluation,we identified important mutation genes that mediate the tumor microenvironment of gastric cancer.According to the previous research results,we further mined the genomic data of gastric cancer and found that ARID1 A and PIK3 CA mutations were significantly related to the tumor microenvironment,which may be the key driving factors of immune activation and T cell infiltration in gastric cancer.5.Based on the tumor microenvironment score system,we found the tumor metabolic features and methylation characteristics related to the tumor microenvironment of gastric cancer.By systematically evaluating the metabolic biological characteristics of gastric cancer patients,we found that kynurenine metabolism was significantly correlated with the immunosuppressive microenvironment.