Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA-activated, catalytic subunit (PRKDC) is an important gene for DNA double-strand break (DSB) repair and central T-cell tolerance. We aimed to investigate the association betweenPRKDCmutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole-exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel-based sequencing data of 3877 solid tumor samples from Geneplus-Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect ofPRKDCmutations on the TME. Four ICI-treated cohorts were analyzed for verifying the correlation betweenPRKDCmutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB inPRKDCmutation samples was significantly higher than inPRKDCwild-type samples (P P < 0.0001, respectively). Further, TCGA datasets showed thatPRKDCmutation samples were associated with a significantly increased expression of CD8(+)T cells, NK cells, immune checkpoint, chemokines, etc. compared toPRKDCwild-type samples (P < 0.05). In ICI-treated cohorts, we also found thePRKDCmutations were associated with increased survival (median PFS, not reached 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, 0.2715-0.9679;P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155-0.841;P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058-0.998;P = 0.050, Hellmann cohort). In summary, we found thatPRKDCmutation often appeared to co-exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.