An Immune Signature for Risk Stratification and Therapeutic Prediction in Helicobacter pylori-Infected Gastric Cancer

SIMPLE SUMMARY: Helicobacter pylori (HP) infection is the greatest risk factor for gastric cancer (GC), and over half of the world’s population is colonized with HP. Up to now, many gene signatures are designed for predicting the prognosis of GC patients, while there are no signatures designed specifically for HP+ GC patients. Considering the tight association between HP infection and tumor immune microenvironment, we constructed an immune-related signature named IRSHG in this study, aiming to provide new insight into the treatment for HP+ GC patients. IRSHG was the first prognostic signature for HP+ GC patients, demonstrating high reliability and feasibility in predicting the prognosis. In addition, IRSHG could help investigate potential therapies and guide anti-PD-1 immunotherapy for HP+ GC patients, providing new insight for the personalized treatment of GC. ABSTRACT: Helicobacter pylori (HP) infection is the greatest risk factor for gastric cancer (GC). Increasing evidence has clarified that tumor immune microenvironment (TIME) is closely related to the prognosis and therapeutic efficacy of HP-positive (HP+) GC patients. In this study, we aimed to construct a novel immune-related signature for predicting the prognosis and immunotherapy efficacy of HP+ GC patients. A total of 153 HP+ GC from three different cohorts were included in this study. An Immune-Related prognostic Signature for HP+ GC patients (IRSHG) was established using Univariate Cox regression, the LASSO algorithm, and Multivariate Cox regression. Univariate and Multivariate analyses proved IRSHG was an independent prognostic predictor for HP+ GC patients, and an IRSHG-integrated nomogram was established to quantitatively assessthe prognostic risk. The low-IRSHG group exhibited higher copy number load and distinct mutation profiles compared with the high-IRSHG group. In addition, the difference of hallmark pathways and immune cells infiltration between the two groups was investigated. Notably, tumor immune dysfunction and exclusion (TIDE) analysis indicated that the low-IRSHG group had a higher sensitivity to anti-PD-1 immunotherapy, which was validated by an external pabolizumab treatment cohort. Moreover, 98 chemotherapeutic drugs and corresponding potential biomarkers were identified for two groups, and several drugs with potential ability to reverse IRSHG score were identified using CMap analysis. Collectively, IRSHG may serve as a promising biomarker for survival outcome as well as immunotherapy efficacy. Furthermore, it can also help to prioritize potential therapeutics for HP+ GC patients, providing new insight for the personalized treatment of HP-infected GC.