title: Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.
abstract: 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.
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel; The Rheumatology Research Center, Hadassah-Hebrew University, Jerusalem, 91120, Israel.
authors: Chamutal
authors: C
authors: Gur
authors: The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel.
authors: Yara
authors: Y
authors: Ibrahim
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
authors: Batya
authors: B
authors: Isaacson
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
authors: Rachel
authors: R
authors: Yamin
authors: The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel.
authors: Jawad
authors: J
authors: Abed
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
authors: Moriya
authors: M
authors: Gamliel
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
authors: Jonatan
authors: J
authors: Enk
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
authors: Yotam
authors: Y
authors: Bar-On
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
authors: Noah
authors: N
authors: Stanietsky-Kaynan
authors: The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel.
authors: Shunit
authors: S
authors: Coppenhagen-Glazer
authors: Department of General Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Noam
authors: N
authors: Shussman
authors: Department of General Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Gideon
authors: G
authors: Almogy
authors: Department of Vascular Biology and Thrombosis Research Medical University of Vienna, 1090, Austria.
authors: Angelica
authors: A
authors: Cuapio
authors: Department of Vascular Biology and Thrombosis Research Medical University of Vienna, 1090, Austria.
authors: Erhard
authors: E
authors: Hofer
authors: The Rheumatology Research Center, Hadassah-Hebrew University, Jerusalem, 91120, Israel.
authors: Dror
authors: D
authors: Mevorach
authors: The Rheumatology Research Center, Hadassah-Hebrew University, Jerusalem, 91120, Israel.
authors: Adi
authors: A
authors: Tabib
authors: Ella Institute of Melanoma, Sheba Medical Center, Ramat-Gan, 526260, Israel.
authors: Rona
authors: R
authors: Ortenberg
authors: Ella Institute of Melanoma, Sheba Medical Center, Ramat-Gan, 526260, Israel.
authors: Gal
authors: G
authors: Markel
authors: Department of Histology and Embryology Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Croatia.
authors: Karmela
authors: K
authors: Miklić
authors: Department of Histology and Embryology Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Croatia.
authors: Stipan
authors: S
authors: Jonjic
authors: Harvard School of Public Health, Boston, MA, 02115, USA.
authors: Caitlin A
authors: CA
authors: Brennan
authors: Harvard School of Public Health, Boston, MA, 02115, USA; Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
authors: Wendy S
authors: WS
authors: Garrett
authors: The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel. Electronic address: giladba@ekmd.huji.ac.il.
authors: Gilad
authors: G
authors: Bachrach
authors: The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel. Electronic address: oferm@ekmd.huji.ac.il.
authors: Ofer
authors: O
authors: Mandelboim
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000382:microbiology*; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000276:immunology* / Q000382:microbiology*; D016967:Fusobacterium nucleatum / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D011971:Receptors, Immunologic; C534712:TIGIT protein, human