Helicobacter pylori and immunotherapy for gastrointestinal cancer

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 vs. 5.03 months, P<0.001; hazards 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 non-exhausted CD8+ T cells, indicative of a "hot" tumor microenvironment. Transcriptomic analysis revealed that H. pylori-positive GC shared similar molecular characteristics to 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 vs. not reached, P=0.042; HR, 2.26; 95% CI, 1.13–4.50; P=0.021 and 5.57 months vs. 6.97 months, P=0.029; HR, 1.59; 95% CI, 1.14–2.23; P=0.006, respectively). The difference of irOS between H. pylori-positive and negative patients had the same trend to 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 microenvironment. However, in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients, H. pylori adversely affects the efficacy of immunotherapy.