Helicobacter pylori and immunotherapy for gastrointestinal cancer

Abstract

Helicobacter pylori infection is associated with the risk of gastrointestinal (GI) cancers; however, its impact on immunotherapy for GI cancers remains uncertain. In this study, we included 10,122 patients who underwent 13C-urea breath tests. Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer (GC) who were treated with anti-PD-1/PD-L1 therapy, H. pylori–positive patients exhibited significantly longer immune-related progression-free survival (irPFS) compared with H. pylori–negative patients (6.97 months versus 5.03 months, p < 0.001, hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62–0.95, p = 0.015). Moreover, the H. pylori–positive group demonstrated a trend of 4 months longer median immune-related overall survival (irOS) than the H. pylori–negative group. H. pylori–positive GC displayed higher densities of PD-L1+ cells and nonexhausted CD8+ T cells, indicative of a “hot” tumor microenvironment. Transcriptomic analysis revealed that H. pylori–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC. However, H. pylori–positive patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS compared with H. pylori–negative patients (16.13 months versus not reached, p = 0.042, HR 2.26, 95% CI 1.13–4.50, p = 0.021 and 5.57 months versus 6.97 months, p = 0.029, HR 1.59, 95% CI 1.14–2.23, p = 0.006, respectively). The difference in irOS between H. pylori–positive and –negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients. We also identified a trend of shorter irPFS and irOS in H. pylori–positive liver cancer and pancreatic cancer patients. In summary, our findings supported that H. pylori infection is a beneficial factor for GC immunotherapy by shaping hot tumor microenvironments. However, in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients, H. pylori adversely affects the efficacy of immunotherapy.