Siglec-7 Mediates Immunomodulation by Colorectal Cancer-Associated Fusobacterium nucleatum ssp. animalis

Abstract

<i>Fusobacterium nucleatum</i> is involved in the development of colorectal cancer (CRC) through innate immune cell modulation. However, the receptors of the interaction between <i>F. nucleatum</i> ssp. and immune cells remain largely undetermined. Here, we showed that <i>F. nucleatum</i> ssp. <i>animalis</i> interacts with Siglecs (sialic acid-binding immunoglobulin-like lectins) expressed on innate immune cells with highest binding to Siglec-7. Binding to Siglec-7 was also observed using <i>F. nucleatum</i>-derived outer membrane vesicles (OMVs) and lipopolysaccharide (LPS). <i>F. nucleatum</i> and its derived OMVs or LPS induced a pro-inflammatory profile in human monocyte-derived dendritic cells (moDCs) and a tumour associated profile in human monocyte-derived macrophages (moMϕs). Siglec-7 silencing in moDCs or CRISPR-cas9 Siglec-7-depletion of U-937 macrophage cells altered <i>F. nucleatum</i> induced cytokine but not marker expression. The molecular interaction between Siglec-7 and the LPS O-antigen purified from <i>F. nucleatum</i> ssp. <i>animalis</i> was further characterised by saturation transfer difference (STD) NMR spectroscopy, revealing novel ligands for Siglec-7. Together, these data support a new role for Siglec-7 in mediating immune modulation by <i>F. nucleatum</i> strains and their OMVs through recognition of LPS on the bacterial cell surface. This opens a new dimension in our understanding of how <i>F. nucleatum</i> promotes CRC progression through the generation of a pro-inflammatory environment and provides a molecular lead for the development of novel cancer therapeutic approaches targeting <i>F. nucleatum</i>-Siglec-7 interaction.