The Analysis Of Immune Heterogeneity Between Pulmonary Adenocarcinoma And Squamous Cell Carcinoma Based On LncRNA Prognostic Model

BackgroundAdenocarcinoma(AD)and squamous cell carcinoma(SCC)are both classified as major forms of non-small cell lung cancer(NSCLC),but differences in clinical prognoses and molecular mechanisms are remarkable.Recent studies have supported the importance of understanding immune status in that it influences clinical outcomes of cancer,and immunotherapies lncluding Immune Checkpoints Inhibitors(ICI)based on the theory of "immune editing" have emerged and made a great successful arising patients’ life.Therefore,it is necessary to investigate the immune status of pulmonary carcinoma,and the research of immune heterogeneity between AD and SCC play an important role in screening NSCLC population who will benefit from ICIs therapy.PurposeThis research aimed to build immune-related prognostic models for AD and SCC cohorts to explore the immunological heterogeneity between them and screen lung caner patients who could benefit from immune therapy.MethodsOur study planed to identify specific long non-coding(lnc)RNAs that control key immune-related genes and to use them to construct risk models for AD and SCC.Risk scores were used to separate patients into high-and low-risk groups,and we validated the prognostic significance of both risk scores with our own cohorts.To study the change of tumor immune microenvironment(TIM)in AD and SCC patients with worse prognosis,we performed many immune evaluation tools,such as Gene Set Enrichment Analysis(GSEA),CIBERSORT and T Cell Immune Dysfunction and Exclusion(TIDE),which can predict response to ICI treatment combining with immunophenoscore(IPS).For lncRNA with great value in prognostic prediction and basic experiment,we upregulated its expression in cancer cell via plasmid transfection,and extracted whole RNA for RNA-seq analysis to screen its potential downstream pathway and target.Results1.Under the standard of closely immune connection and prognostic significance,there were 12 lncRNAs for AD and 4 lncRNAs for SCC to build the prognostic risk models.And for both cancer types,the significant difference of prognosis and immune response between high-and low-risk groups.2.For AD patients,GSEA suggested that the immune responses of patients in the high-risk group tended to be weakened.Considering the clinical feature,the immunity of AD patients decreased progressively along with tumor progression.Evaluation of immune infiltration based on CIBERSORT revealed that the decreasing degree of infiltration of dendritic cells(p<0.001)was an important feature for immunological alteration,which might cause the inactivation of immune response in high-risk AD patients.TIDE score indicated that deterioration of the TIM is due mainly to T cell exclusion in AD patients(1.630 vs 1.245,p<0.0001).3.The situation in SCC patients was opposed.Immune response in high-risk group is stronger than low-risk.However,TIDE result indicated CD8+T cell was limited by TIM in high-risk patients(1.382 vs 0.634,p=0.007).Hence,although patients in high-risk group possessed active immune response and infiltrated CD8+T cell,the dysfunction of CD8+T cell accede accelerated tumor progression.4.In AD cohort,there was no significant result between high-and low-risk group in IPS comparation,which mean high-risk patients could not get more benefit from ICI treatment than low-risk patients.But IPS of high-risk patients with SCC was much more than low-risk group(p<0.0001),which indicated that SCC patients in high-risk group belonged to beneficial population of ICI therapy.5.To expand the subsequent basic experiment,we made the prediction of downstream targets via The Cancer Proteome Atlas and RNA-seq analyses of a transfected lung cancer cell line indicated that the lncRNA LINC00996 was a potential therapeutic target in AD and worth for further research.Conclusion1.Our research proved that AD and SCC,as the major two pathological types of NSCLC,possessed different immune microenvironment components and variety immune deterioration mechanisms.The significant immune heterogeneity existed.2.High-risk group of AD cohort exhibited low immune response and T cell exclusion TIM,which were not ICI therapy beneficial population.However,high-risk patients with SCC possessed active immune response and T cell dysfunction TIM,who could benefit from ICI therapy.