Analysis of the interaction of Fusobacterium nucleatum and CEACAM1 and its impact on antitumor immunity

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Fusobacterium nucleatum is a gram-negative anaerobic bacterium primarily found in the oral cavity. In recent years, it has gained increasing attention for its association with colorectal carcinoma and corresponding distant metastases. Several mechanisms were discovered by which F. nucleatum impacts the tumor microenvironment. Intriguingly, F. nucleatum was reported to protect tumor cells from immune cell killing. Mechanistically, engagement of the inhibitory receptor TIGIT expressed by NK and T cells was observed to inhibit antitumor immunity. Very recently, F. nucleatum was also found to specifically bind to CEACAM1, an inhibitory transmembrane protein expressed by epithelial and immune cells. Our central hypothesis is, that the interaction between F. nucleatum and CEACAM1 inhibits immune cell-mediated killing of tumor cells in the tumor microenvironment of colorectal cancer. Thus, the aim of this research project is to elucidate the effect of bacterial engagement of CEACAM1 on tumor cell killing in the tumor microenvironment. In the first part, F. nucleatum mutants deficient in binding CEACAM1 will be generated and the recently identified trimeric autotransporter adhesin will be confirmed as the fusobacterial ligand for CEACAM1. In the second part, it will first be tested whether binding to CEACAM1 is conserved among clinical strains of F. nucleatum isolated from human colorectal carcinoma specimens. In addition, the effect of F. nucleatum binding to CEACAM1 on antitumor immunity by tumor infiltrating lymphocytes will be investigated. Finally, using transgenic mice expressing human CEACAM1, the impact of F. nucleatum binding to CEACAM1 on tumor growth in vivo will be assessed.In summary, this project will decipher the influence of the F. nucleatum – CEACAM1-interaction on antitumor immunity in the tumor microenvironment. Our long-term aim is to translate these findings into new targeted therapies to activate antitumor immunity.