Prognostic And Predictive Roles Of TMB And CNA Across Metastatic Pan-cancer:immunotherapeutic Implications

BackgroundIn recent years,immunological checkpoint inhibitors(ICIs)represented by PD-1/PD-L1 antibodies have made significant progress in various tumor treatments.However,the overall low efficiency and cost limits the clinical application of such drugs.Finding accurate predictive markers of curative effect has become an urgent problem in the field of tumor immunotherapy.Currently,the ability of tumor mutation load(TMB)to predict the efficacy of immunological checkpoint inhibitors has been validated in several clinical trials.However,the inspection and analysis methods of TMB,the determination of cutoff value,and the predictive efficacy of TMB alone have become the limiting factors for clinical application.In particular,more and more clinical and experimental data show that the predictive power of single therapeutic markers is limited,and the combination of markers can better characterize the efficacy of immunological checkpoints in terms of predictive efficacy and principle.Copy number variation(CNA)is associated with tumor immune escape and tumor immune infiltration and is a negative factor in tumor immunotherapy.The aim of this study was to investigate the significance of the combined biomarkers based on TMB and copy number variation(CNA)for the prognosis and prediction of ICI therapy in metastatic pan-tumor and the molecular biological characteristics of the population carrying the marker.MethodsFirstly,MSK-IMPACT data was used as a set of exploration to analyze the prognostic impact of TMB or CNA single factor on patients;then the TCGA data was used as a validation set to analyze the prognostic impact and molecular biological characteristics of the two factors.The independent cohort of PD-1 treatment was used to analyze the predictive efficacy of TMB and CNA alone and in combination,and to further compare the predictive efficacy and molecular characteristics of specific subgroups of TMB combined with CNA.ResultsTMB combined with CNA has a good predictive effect on a variety of tumor prognosis,and most patients with TMBlowCNAlow have a higher survival rate.In predictive analysis,both TMB and CNA are independent predictors of ICI.It is worth noting that when TMB and CNA were combined,TMBhighCNAlow patients responded better to ICI in all three cohorts compared to the other subgroups.At the same time,the TMB-CNA combination has a significant advantage in predicting ICI efficacy compared to TMB alone or CNA.In addition,analysis of the TCGA and MSK-IMPACT databases indicated that the combined distribution of TMB and CNA is consistent with the effect of known tumor types on immunotherapy.In addition,the use of the TCGA database also revealed the molecular characteristics of TMB and CNA alone or in combination,indicating that the reason for the poor immunological efficacy of some patients with high TMB is related to the immune escape caused by CNA.ConclusionsWe have demonstrated for the first time that TMB combined with CNAcan predict a variety of tumor prognosis and clinical response to immunotherapy.TMBhigh CNA low cancer patients receive the best immunotherapy,and some patients with TMBhigh’s immunological efficacy may be related to the immune escape caused by CNA.The above findings have certain significance for more accurate prediction of the benefit of immunotherapy,and provide further ideas for the study of immunological efficacy combined with predictive markers.