Journal
IMMUNITY
Volume 42, Issue 2, Pages 344-355Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.01.010
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Funding
- European Research Council under the European Union's Seventh Framework Programme (FP) / ERC [320473-BacNK]
- I-CORE Program of the Planning and Budgeting Committee
- Israel Science Foundation
- I-Core on Chromatin and RNA in Gene Regulation
- GIF Foundation
- Lewis family Foundation
- ICRF professorship grant
- Israeli Science Foundation
- Helmholtz Israel grant
- Rosetrees Trust
- ICRF project grant
- Israeli Science Foundation (Morasha)
- Foulkes Foundation
- Hoffman-LaRoche
- Marie Curie European Research Council program [FP7-MC-ITN-317013-NATURIMMUN]
- ERC Advanced Grant [322693]
- [R01CA154426]
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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, tumorimmune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleatum to inhibit immune cell activity via TIGIT.
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