Investigation And Mechanism Exploration On The Association Of PRKDC Mutation And Response To Immune Checkpoint Inhibitors In Advanced Solid Tumors

PurposeTo investigate the association between PRKDC mutation and tumor mutation burden(TMB),tumor microenvironments(TME),and response to immune checkpoint inhibitors(ICIs)in solid tumors.Method The whole exome sequencing data of 4023 pan-cancer(the top 10 cancer types with the highest PRKDC mutation rate)solid tumor samples from the Cancer Genome Atlas(TCGA)and the panel-based sequencing data of 3877 pan-cancer(a total of 8cancer types)solid tumor samples from Gene Plus-Beijing,China were used to analyze the association of PRKDC mutation and TMB.The RNA sequencing(RNA-seq)data of 3541 solid tumor samples from TCGA was used to explore the association of PRKDC mutation with the m RNA expression level of immune-related cells in TME.The two ICIs-treated cohorts,Hellmann’ non-small cell lung cancer(NSCLC)cohort and Allen’ melanoma cohort,were used to analyze the correlation between PRKDC mutation and the response to ICIs.Result In TCGA datasets,the TMB in PRKDC mutation samples was significantly higher than PRKDC wild-type samples in each cancer type except for cholangiocarcinoma(P<0.05).In Gene Plus-Beijing pan-cancer datasets,we also found that the TMB in PRKDC mutation samples were significantly higher than PRKDC wild-type samples(Median TMB,17 vs.6;P < 0.0001).Further,in TCGA datasets,it showed that PRKDC mutation samples were associated with significant expression increase of CD8+ T cells,cytotoxic T cells,NK cells,immune-checkpoint,chemokines etc compared to PRKDC wild-type samples(P<0.05).In ICIs-treated cohorts,we also found the PRKDC mutation was associated with superior survival(median PFS,not reached(NR)vs.6.8 months HR,0.2893 95% CI,0.1255-0.6672 P=0.0650,Hellmann cohort;median OS,1184 days vs.250 days HR,0.5126 95% CI,0.2715-0.9679P=0.1020,Allen cohort),and the superiority was significantly in COX proportional hazard model(HR,0.361 95% CI,0.155-0.841;P = 0.018,Allen cohort;HR,0.24095% CI,0.058-0.998;P = 0.050,Hellmann cohort).Conclusion In pan-cancer solid tumor patients,PRKDC mutations are associated with an increased TMB and an inflamed TME.In NSCLC and melanoma patients,PRKDC mutations are associated with a better response to ICIs,and it’s an independent prognostic factor for ICIs treatment.PRKDC mutation may be a potential predictive biomarker for ICIs-immunotherapy.