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DNA Damage and Repair Biomarkers of Immunotherapy Response.

ABSTRACT: DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675-93. ©2017 AACR.

SUBMITTER: Mouw KW

PROVIDER: S-EPMC5659200 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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DNA Damage and Repair Biomarkers of Immunotherapy Response.

Mouw Kent W KW Goldberg Michael S MS Konstantinopoulos Panagiotis A PA D'Andrea Alan D AD

Cancer discovery 20170619 7

DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to ...[more]

PMID: 28630051

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Project description:Immune checkpoint inhibitors(ICIs) that activate tumor-specific immune responses bring new hope for the treatment of hepatocellular carcinoma(HCC). However, there are still some problems, such as uncertain curative effects and low objective response rates, which limit the curative effect of immunotherapy. Therefore, it is an urgent problem to guide the use of ICIs in HCC based on molecular typing. We downloaded the The Cancer Genome Atlas-Liver hepatocellular carcinoma(TCGA-LIHC) and Mongolian-LIHC cohort. Unsupervised clustering was applied to the highly variable data regarding expression of DNA damage repair(DDR). The CIBERSORT was used to evaluate the proportions of immune cells. The connectivity map(CMap) and pRRophetic algorithms were used to predict the drug sensitivity. There were significant differences in DDR molecular subclasses in HCC(DDR1 and DDR2), and DDR1 patients had low expression of DDR-related genes, while DDR2 patients had high expression of DDR-related genes. Of the patients who received traditional treatment, DDR2 patients had significantly worse overall survival(OS) than DDR1 patients. In contrast, of the patients who received ICIs, DDR2 patients had significantly prolonged OS compared with DDR1 patients. Of the patients who received traditional treatment, patients with high DDR scores had worse OS than those with low DDR scores. However, the survival of patients with high DDR scores after receiving ICIs was significantly higher than that of patients with low DDR scores. The DDR scores of patients in the DDR2 group were significantly higher than those of patients in the DDR1 group. The tumor microenvironment(TME) of DDR2 patients was highly infiltrated by activated immune cells, immune checkpoint molecules and proinflammatory molecules and antigen presentation-related molecules. In this study, HCC patients were divided into the DDR1 and DDR2 group. Moreover, DDR status may serve as a potential biomarker to predict opposite clinical prognosis immunotherapy and non-immunotherapy in HCC.

Project description:The DNA damage repair (DDR) pathway is one of the pathways of tumor pathogenesis, but its relationship with the immunophenotype has not been clarified in colon cancer (CC). We identified the differentially expressed immune-related genes (DEIRGs) between two DDR molecular subtypes, namely, C1 and C2, and used univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) penalized Cox regression analysis to construct the risk score in the training cohort [n=1,009, a combination of The Cancer Genome Atlas (TCGA) and GSE39582]. Regarding the median risk score as the unified cutoff to classify the patients into high- and low-risk groups. Two independent cohorts (GSE17538, n=232; GSE38832, n=122) were used for external validation of the prognostic value of the risk score. The IMvigor210 cohort (n=348) was used to test the predictive value of the risk score for immunotherapy response. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were performed to discover the underlying mechanism. Immune cell infiltration was quantified by the single sample gene set enrichment analysis (ssGSEA) algorithm. The high-risk group showed significantly reduced overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), progression-free survival (PFS), and relapse-free survival (RFS) compared to the low-risk group, and the two groups differed significantly in lymphatic invasion, American Joint Committee on Cancer (AJCC) TNM stage, preoperative carcinoembryonic antigen (CEA) level, etc. The enrichment levels of pathways related to colorectal cancer, epithelial-mesenchymal transition (EMT), angiogenesis, hypoxia, P53, TGF-β, KRAS signaling, etc., were upregulated in the high-risk group, but DDR-related pathways were defective in the high-risk group. The immunophenotypes of the high-risk group tended to be desert and excluded, and the risk score of patients who responded to immunotherapy was significantly lower than that of patients who did not respond to immunotherapy. The higher the infiltration levels of gamma delta T cells (γδ T cells), immature dendritic cells, and T follicular helper (Tfh) cells, the more significant adverse impact on the prognosis of CC patients was exhibited and an obviously positive correlation with the risk score was showed. An immune gene risk score associated with the DDR molecular subtype was built and verified herein; that is applicable to the prognosis and immunotherapy response prediction in CC.

Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma with relatively poor clinical outcomes DNA damage repair genes (DDRGs) as potential biomarkers are rarely reported in predicting immunotherapy response and clinical prognosis for ccRCC. Methods: RNA-seq and clinical data of ccRCC cohort were collected form TCGA database. Univariate Cox regression and LASSO analysis were performed to construct a DDRG risk signature. Functional enrichment analysis was performed to explore latently enriched pathways associated with DDRG signature. Immune cell infiltration level was estimated using gene set enrichment analysis, and immune response of ccRCC was predicted by tumor immune dysfunction and exclusion (TIDE) algorithm. To predict 1-, 3-, and 5-years overall survival (OS), a nomogram was constructed based on independent prognostic factors, whose performance would be evaluated by calibration curve. Results: A total of 47 DNA damage repair related genes (DDRGs) with significant prognostic value were identified in the ccRCC cohort (n = 519). A DDRG risk signature comprising six DRRGs (MSH3, RAD54L, RAD50, EME1, UNG, and NEIL3) were constructed by the LASSO analysis. ccRCC patients were then divided into low- and high-risk groups based on the risk score. Survival analysis revealed that patients in high-risk groups exhibited significantly poorer OS and progression-free survival (PFS), as was confirmed by the testing dataset. Functional enrichment analysis indicated that differentially expressed genes (DEGs) between high- and low-risk groups were mainly associated with immune-related biological processes in ccRCC, among which the immunodeficiency pathway was significantly enriched in the high-risk group. Though the risk signature was significantly correlated with the immune cell infiltration, PD-1 and PD-L1 were less expressed in the DDRG signature, which might indicate the poor response to immunotherapy in the high-risk group. Furthermore, the Cox regression analysis indicated that the DDRG signature can be served as an independent prognostic predictor when compared to clinical characteristics. Based on the independent prognostic predictors, we constructed a nomogram with excellent predictive ability in OS prediction for ccRCC patients. Conclusion: We developed a reliable DDRG risk signature that can independently predict the OS and PFS of ccRCC, which is also promising for predicting immunotherapeutic responses in ccRCC patients.

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DNA Damage and Repair Biomarkers of Immunotherapy Response.

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DNA Damage and Repair Biomarkers of Immunotherapy Response.

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