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

Binbin Yuan; Chengfei Jiang; Lingyan Chen; Lihui Wen; Jinlong Cui; Min Chen; Shu Zhang; Lin Zhou; Yimeng Cai; Jian-Hua Mao; Xiaoping Zou; Bo Hang; Pin Wang

doi:10.3389/fcell.2022.893546

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

Front Cell Dev Biol. 2022 May 23:10:893546. doi: 10.3389/fcell.2022.893546. eCollection 2022.

Authors

Binbin Yuan¹, Chengfei Jiang¹, Lingyan Chen¹, Lihui Wen², Jinlong Cui³, Min Chen¹, Shu Zhang¹, Lin Zhou¹, Yimeng Cai⁴, Jian-Hua Mao⁵, Xiaoping Zou¹, Bo Hang⁵, Pin Wang¹

Affiliations

¹ Department of Gastroenterology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
² Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
³ Berkeley-Nanjing Research Center, Nanjing, China.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States.
⁵ Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.

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).

Keywords: DNA repair gene signature; gastric cancer; immune checkpoint blockade; immune checkpoint inhibitors; immunotherapy; prognostic biomarker; score system.