DNA Damage Repair Status Predicts Opposite Clinical Prognosis Immunotherapy and Non-Immunotherapy in Hepatocellular Carcinoma

Abstract

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.

DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

“…DNA damage response dysregulation is often enhanced in HCC, resulting in poor response to DNA-damaging anticancer therapies [ 25 ]. Researchers observed that high-repair HCC tumors treated with conventional chemotherapy resulted in worse overall survival than high-repair-status patients who received immune checkpoint inhibitors [ 81 ]. The assessment of DNA damage and repair dysregulation may pose another method of stratifying patients based on DNA repair status for improved treatment management and selection.…”

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…In HCC, the proportion of activated immune cells increases significantly in patients with a high expression of DDR-related genes (DDR2) [ 71 , 72 ]. The subtype of activated DDR has demonstrated significantly increased expression of the immune checkpoint, and its immune score was significantly higher than that of the low expression group [ 72 ]. In addition, it is important to note that mutations or defects in the DDR signaling pathway genes are associated with altered immune cell infiltration.…”

“…However, the use of individual DDR pathway changes in guiding ICIs treatment remains to be explored [20,47,69]. Researchers have established reliable DDR scoring models and effectively analyzed the predictive effect of co-mutation, the DDR gene models of various researchers can effectively predict specific response to ICIs treatment [69][70][71][72]. In one case, Yi-Ru Pan et al selected 18 DDR genes as the defined gene panel and achieved a predicted response rate of about 60% in patients with DDR mutations [73].…”

Patient-Level DNA Damage Repair Pathway Profiles and Anti-Tumor Immunity for Gastric Cancer

“…Accordingly, increased levels of TLS, especially infiltration of CD8+ T cells, were related to the high DDR signature scores. The increased lymphocyte infiltration usually means a superior prognosis and a potent anti-tumor immune response ( 68 ), indicating the immune-hot status in tumors with high signature scores. However, tumors with low DDR pathway signature scores were enriched with fibroblasts and endothelial cells, together with the TGF-β signaling pathway activation, corresponding to an immune-cold phenotype ( 69 , 70 ).…”