Secretory IgA dysfunction underlies poor prognosis in Fusobacterium-infected colorectal cancer [normal colon tissue]

Fusobacterium nucleatum (Fn), enriched in human colorectal cancer (CRC), is linked to a worse prognosis. To uncover the cellular and molecular mechanisms behind this Fn-associated prognostic effect, we conducted single-cell transcriptomic analyses on 42 surgically removed colon tissues from newly diagnosed colon cancer patients. Through single-cell and spatial transcriptome data analyses, we found that the development of IgA plasma cells producing functional secretory IgA was impaired due to disrupted communications between IgA plasma cells and macrophages in Fn-positive CRC. Additionally, we identified a dysregulated IgA maturation (IGAM) module in Fn-positive patients, indicating compromised IgA-mediated mucosal immunity. This finding was further supported by observed increases in bacterial infiltration within tumors of Fn-positive patients. Remarkably, we were able to stratify Fn-positive patients based on IGAM activity, which could lead to novel treatment strategies for Fn-positive CRC patients. Our findings indicate that impaired secretory IgA activity by Fn infection increases the bacterial burden within tumors and worsens prognosis through chronic inflammation. Additionally, identifying a novel gene expression biomarker for stratifying Fn-positive patients promises to refine CRC treatment strategies, offering a more tailored approach to patient care. To examine the influence of Fn in the colon under monocolonization, we designed an in vivo experiment using germ-free (GF) mice. Six-week-old female GF mice with a C57BL/6 background were used in all experiments. Ten mice were randomly divided into two groups (5 mice per group) including control group and Fn group. GF mice were fasted for 2 hours prior to oral gavage. Fn group received an oral administration of 1 × 10⁹ colony-forming units (CFU) in 200 µL of PBS, while the control group received an equivalent volume of PBS alone, three times per week for 5 weeks. At the end of the experiment, the GF mice were sacrificed, and colon tissues were collected from control (n=5) and Fn (n=5) groups. Dissected colon tissues from PBS control (n=5) and Fn-treated (n=5) GF mice were pooled for each group.