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Immunity. 2015 Feb 17;42(2):344-355. doi: 10.1016/j.immuni.2015.01.010. Epub 2015 Feb 10.

Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.

Author information

1
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.
2
The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel.
3
The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC Jerusalem, 91120, Israel.
4
Department of General Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
5
Department of Vascular Biology and Thrombosis Research Medical University of Vienna, 1090, Austria.
6
The Rheumatology Research Center, Hadassah-Hebrew University, Jerusalem, 91120, Israel.
7
Ella Institute of Melanoma, Sheba Medical Center, Ramat-Gan, 526260, Israel.
8
Department of Histology and Embryology Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Croatia.
9
Harvard School of Public Health, Boston, MA, 02115, USA.
10
Harvard School of Public Health, Boston, MA, 02115, USA; Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
11
The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel. Electronic address: giladba@ekmd.huji.ac.il.
12
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.

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.

PMID:
25680274
PMCID:
PMC4361732
DOI:
10.1016/j.immuni.2015.01.010
[Indexed for MEDLINE]
Free PMC Article

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