Efficacy Of Immunotherapy And Its Potential Mechanism In ARID1A-mutant Solid Tumors

Purpose: Immune checkpoint inhibitors(ICIs)have achieved a good partial response in various solid tumors,leading to better treatment options for tumor patients.At present,the common biomarkers for ICIs include programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1),tumor mutation burden(TMB)and microsatellite instability(MSI).However,the objective response rate(ORR)of immunotherapy remains suboptimal,with only a minority of advanced patients benefiting from ICIs.Predicting response to ICIs and overcoming the narrow therapeutic window remain the greatest challenges in clinical application.Therefore,we collected clinical information of patients with ARID1 A mutated tumors and analyzed the mutated characteristics,the efficacy and prognosis of immunotherapy,and aimed to explore the potential mechanism of ARID1 A mutation as a biomarker for predicting immunotherapy.Methods: Thirty-five tumor patients harboring ARID1 A mutations were retrospectively studied from the Affiliated Hospital of Qingdao University from January 2020 to December 2022.The age,gender,pathological type,tumor staging,PD-L1 expression,MSI status,treatment,concurrent genomic alterations by next-generation sequencing(NGS)were retrospectively obtained t in the YIDUCLOUD system.The survival status and survival time of patients were followed up.The treatment efficacy was evaluated according to Response evaluation criteria in solid tumors(RECIST1.1)via imaging data.The primary endpoint was ORR and disease control rate(DCR),and the secondary endpoint was overall survival(OS).The Kaplan-Meier method was used to plot the survival curves and the Log-Rank method was used to test the survival differences.Differentially expressed genes(DEGs)between ARID1 A mutant and wild type tissues of gastric cancer(GC)patients were screened in mu Target,an online database,for functional enrichment analysis.Finally,bioinformatics analysis of the expression of immune checkpoint and immune cell infiltration levels in ARID1 A mutant GC was performed.Results: Of the 35 patients with ARID1 A mutations enrolled,ARID1 A mutations were often co-mutated with TP53 in 51.43% of patients,and ARID1 A mutations were often accompanied by DNA damage repair(DDR)genes co-mutations.Of the 23 patients received immunotherapy,17 patients had assessable lesions,with an objective response rate of 30.43%(7/23)and the disease control rate of 65.22%(15/23).The other 6 patients received maintenance therapy with ICIs after surgery,1 of whom had disease progression due to increased cancerous ascites,and none of the other 5 patients had an assessable lesion.In addition,the median OS(m OS)of ARID1 A mutated patients received ICIs was51.07 months,and that of mutant patients who did not receive immunotherapy was 41.44 months,with a statistically significant difference in survival between two group(m OS:51.07 months vs 41.44 months,P=0.046).The correlation between ARID1 A mutation and MSI-H,TMB and EBV infection in GC patients was further determined.Finally,ARID1 A mutations status was considered to be highly correlated with high expression of immune checkpoints and expression of tumor infiltrating lymphocytes(TILs)levels.Conclusion: Tumor patients with ARID1 A mutations may have better clinical outcomes from immunotherapy,especially in GC patients.ARID1 A alterations affect genomic stability and tumor immune microenvironment(TIME)and can be used as a predictive biomarker for immunotherapy.