A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer

Abstract

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).

A novel DNA damage repair-related gene signature predicting survival, immune infiltration and drug sensitivity in cervical cancer based on single cell sequencing

“…Our study found that compared with the high DDR group, the low DDR group had stronger immune cell infiltration, with immunosuppressive cells such as NK cells and M2 macrophages enriched in the high DDR group, leading to poorer prognosis, while the activated T cells and B cells were more abundant in the low DDR group, resulting in a better prognosis. Moreover, in gastric cancer and melanoma, it has also been found that patients with low DDR scores have significantly increased immune infiltration, consistent with our results ( 43 , 44 ). Studies have shown that changes in tumor DDR pathways are significantly correlated with the response to immune checkpoint inhibitors (ICIs) and can also affect patient survival ( 45 – 48 ).…”

“…significantly increased immune infiltration, consistent with our results (43,44). Studies have shown that changes in tumor DDR pathways are significantly correlated with the response to immune checkpoint inhibitors (ICIs) and can also affect patient survival (45-48).…”

Biomarkers for immune checkpoint inhibition in sarcomas – are we close to clinical implementation?

“…In several cancers, various GES have been found to be capable of predicting ICI response, including in melanoma [ 115 – 117 ], NSCLC [ 118 – 121 ], gastric cancer [ 122 ], lower-grade glioma [ 123 ] and some across multiple cancer types such as in both NSCLC and melanoma [ 124 ]. In addition, a pan-tumor signature predictive of ICI response was derived from 220 patients across HNSCC, gastric cancer, triple-negative breast cancer, bladder, anal canal, biliary, colorectal, esophageal, and ovarian cancers.…”

Multigene Expression Biomarkers and Score Systems for Predicting Therapeutic Benefit in Gastrointestinal Cancers

“…For example, as recent evidence revealed, DNA repair landscape is a significant factor in driving response to immune checkpoint blockade therapy (27). We developed a novel 15-DNA repair gene signature (DRGS) and scoring system to evaluate its efficiency in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric cancer (28). Multi-omics data analysis demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and such patients exhibited a longer overall survival and may benefit more from immune checkpoint blockade therapy, as compared to the low-score patients (28).…”