Association of Fusobacterium nucleatum with suppressed anti-tumor T cell responses in gastric cancer

Background Gastric cancer is etiologically linked to pathogenic microbes. Fusobacterium nucleatum in gastric cancer-associated microbiota is associated with high tumor mutation burden and poor prognosis. F. nucleatum was also shown to suppress anti-tumor immune response in colorectal cancer. The aim of this study is to identify the F. nucleatum -induced change in the immune microenvironment of gastric cancer. Materials Resected gastric cancer specimens and endoscopic-extracted biopsies were obtained from Human Biobank of Chiayi Chang Gung Memorial Hospital. The presence of F. nucleatum in the specimens was determined by nested PCR. Resected specimens were analyzed by transcriptomic analysis. In vitro experiment using F. nucleatum -infected gastric cancer cell lines was utilized to identify deregulated genes in the cancer cells by F. nucleatum infection. Results Helicobacter pylori infection was significantly declined among gastric cancer patients in Southwestern Taiwan. Conversely, F. nucleatum was identified in nearly 50% of patients, emerging as the dominant oncogenic infection. Transcriptomic and ontological analyses of resected specimens revealed that F. nucleatum correlates with increased T cell markers, including T cell receptor constant region and CD3E . T cell receptor subunit levels correlated with CD8A , indicating cytotoxic T cell infiltration in F. nucleatum -positive lesions. However, upregulation of negative regulators LAX1 and PRDM1 , proportional to CD3E and CD8A , suggests these abundant T cells are inactive. In vitro , F. nucleatum-induced CXCL9 and CXCL10 upregulation in select gastric cancer cell lines. Correspondingly, CXCL9 and CXCL10 were elevated and highly correlated with CD3E and CD8A in a subset of F. nucleatum -positive specimens. Conclusions F. nucleatum infection in gastric cancer increased drastically in Taiwan. Higher abundance of cytotoxic T cells is associated with F. nucleatum , likely being attracted to tumor sites by F. nucleatum -induced CXCL9 and CXCL10 . However, despite being attracted to gastric tumor sites, these tumor-infiltrating cytotoxic T cells are inactive and exhibit an exhausted phenotype, indicating that F. nucleatum is associated with an immunosuppressive microenvironment. Our finding suggest that targeting F. nucleatum could promote anti-tumor immune response and subsequently the treatment efficacy.