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

Abstract

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 between PRKDC mutations 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 of PRKDC mutations on the TME. Four ICI‐treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild‐type samples (P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8+ T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild‐type samples (P < 0.05). In ICI‐treated cohorts, we also found the PRKDC mutations 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 that PRKDC mutation 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.

Role of PRKDC in cancer initiation, progression, and treatment

“…The mutation rate of PRKDC and the expression level of DNA-PKcs in various tumors are quite different. Chen et al [ 37 ] conducted statistical analysis on the mutation rate of PRKDC as reported in the Cancer Genome Atlas (TCGA) and the Chinese population database; the authors found that PRKDC had a high mutation rate in several tumors, such as colorectal cancer, gastric cancer, and endometrial cancer, with a high correlation with microsatellite instability. In the TCGA database, PRKDC mutations were found in 51 (9.66%) of 528 colorectal cancers, 42 (9.63%) of 436 gastric cancers, and 23 (9.27%) of 248 endometrial cancers.…”

“…Immunotherapies have received increasing attention in recent years, and among the most important ones are the immune checkpoint inhibitor (ICI) therapies [ 70 , 71 ]. Currently, an important factor in predicting the response to ICIs is tumor mutation burden (TMB) [ 37 ], which refers to the number of nonsynonymous mutations per million bases of the tumor cell genome. The damage to the DDR system is closely related to the TMB, and a functional defect of the DDR system leads to increased genomic instability and accumulation of mutations in cells [ 37 ].…”

Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

“…These findings highlight PRKDC mutation as a potential biomarker for immunotherapy. Moreover, Chen et al recently investigated the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI by integrated analysis of sequencing data of solid tumors in TCGA ( n = 4023) and Geneplus ( n = 3877) [ 57 ]. They showed that PRKDC mutant tumors have significantly higher TMB than that of PRKDC wild-type tumors.…”

“…Further, solid tumors harboring PRKDC mutations were enriched in tumor immunogenicity microenvironments, such as CD8+ T cells, NK (natural killer) cells, and chemokines. Importantly, PRKDC mutations were associated with better survival in patients after ICI treatment [ 57 , 58 ]. These results support the use of PRKDC mutations as a stratification marker for immunotherapy.…”

Potential Value of PRKDC as a Therapeutic Target and Prognostic Biomarker in Pan-Cancer

“…We found that over 18% of UCEC patients and about 12% of STAD patients presented alteration in PRKDC and the alteration correlates with better survival. In a recent study (31), PRKDC mutation was found to be related to higher TMB, elevated mRNA levels of immunity-related genes as well as improved response to ICI (immune checkpoint inhibitor) treatments in tumor individual. Another publication also discovered that PRKDC mutation was linked to an advanced TMB and MSI states in tumors, and knocked down PRKDC or used a DNA-PKcs inhibitor might improve ICI e cacy (32).…”