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

By C. Gur, Y. Ibrahim, Batya Isaacson, Rachel Yamin, Jawad Abed, M. Gamliel, Jonatan Enk, Y. Bar-On, Noah Stanietsky-Kaynan, S. Coppenhagen-Glazer and 14 more. Immunity, 2015

1,297 citations recorded by the source corpus.

SUMMARY Bacteria, such as Fusobacterium nucleatum, are present in the tumor microenvironment. However, the immunological consequences of intra-tumoral bacteria remain unclear. Here, we have shown that natural killer (NK) cell killing of various tumors is inhibited in the presence of various F. nucleatum strains. Our data support that this F. nucleatum-mediated inhibition is mediated by human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cells and on various T cells. Using a library of F. nucleatum mutants, we found that the Fap2 protein of F. nucleatum directly interacted with TIGIT, leading to the inhibition of NK cell cytotoxicity. We have further demonstrated that tumor-infiltrating lymphocytes expressed TIGIT and that T cell activities were also inhibited by F. nucleatum via Fap2. Our results identify a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleatum to inhibit immune cell activity via TIGIT.

View Paper: https://www.semanticscholar.org/paper/8f3624f137107127c5614b7e5ef8e701c3891492

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Citations in the corpus

• Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects. (2016, background): “…microbes can directly be transforming agents (Sears and Garrett, 2014) by providing a toxic metabolite, an oncogenic product or inducing an inflammatory milieu which will culminate in genomic instability and/or DNA damage responses and/or immune escape (Gur et al., 2015; Louis et al., 2014).”
• Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc (2016, background): “F. nucleatum also suppresses anti-tumor immunity and inhibits tumor killing by natural killer (NK) cells (Gur et al., 2015).”
• Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 (2019, background): “and his co-works discovered that TIGIT could directly bind to the Fap2 protein derived from Fusobacterium nucleatum, triggering a negative signal to suppress the activities of NK cells and T cells, and hence mediating a tumor-immune evasion mechanism [107].”
• Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation (2016, background): “The suppressive function of TIGIT is also exploited by Fusobacterium nucleatum, a bacterium often found within the tumor microenvironment, to inhibit protective immune responses (Gur et al., 2015).”