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

Chamutal Gur, Yara Ibrahim, Batya Isaacson, Rachel Yamin, Jawad Abed, Moriya Gamliel, Jonatan Enk, Yotam Bar-On, Noah Stanietsky-Kaynan, Shunit Coppenhagen-Glazer, Noam Shussman, Gideon Almogy, Angelica Cuapio, Erhard Hofer, Dror Mevorach, Adi Tabib, Rona Ortenberg, Gal Markel, Karmela Miklić, Stipan JonjicCaitlin A. Brennan, Wendy S. Garrett, Gilad Bachrach*, Ofer Mandelboim

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

837 Scopus citations

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. Ourdata support that this F.nucleatum-mediated inhibition is mediated by human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cellsand on various Tcells. 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 Tcell 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.

Original languageAmerican English
Pages (from-to)344-355
Number of pages12
JournalImmunity
Volume42
Issue number2
DOIs
StatePublished - 17 Feb 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

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