Binding of the Fap2 Protein of Fusobacterium nucleatum to Human Inhibitory Receptor TIGIT Protects Tumors from Immune Cell Attack

Bacteria,suchasFusobacteriumnucleatum,arepre-sent in the tumor microenvironment. However, theimmunological consequences of intra-tumoral bac-teria remain unclear. Here, we have shown that natu-ral killer (NK) cell killing of various tumors is inhibitedin the presence of various F. nucleatum strains.Our data support that this F. nucleatum-mediatedinhibition is mediated by human, but not by mouseTIGIT, an inhibitory receptor present on all humanNK cells and on various T cells. Using a library ofF. nucleatum mutants, we found that the Fap2 pro-tein of F. nucleatum directly interacted with TIGIT,leading to the inhibition of NK cell cytotoxicity. Wehave further demonstrated that tumor-infiltratinglymphocytes expressed TIGIT and that T cell activ-ities were also inhibited by F. nucleatum via Fap2.Our results identify a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploitthe Fap2 protein of F. nucleatum to inhibit immunecell activity via TIGIT.