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 Jonjic; Caitlin A. Brennan; Wendy S. Garrett; Gilad Bachrach; Ofer Mandelboim

doi:10.1016/j.immuni.2015.01.010

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 journal › Article › peer-review

906 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 language	English
Pages (from-to)	344-355
Number of pages	12
Journal	Immunity
Volume	42
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2015.01.010
State	Published - 17 Feb 2015

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Publisher Copyright:
© 2015 Elsevier Inc.

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Gur, C., Ibrahim, Y., Isaacson, B., Yamin, R., Abed, J., Gamliel, M., Enk, J., Bar-On, Y., Stanietsky-Kaynan, N., Coppenhagen-Glazer, S., Shussman, N., Almogy, G., Cuapio, A., Hofer, E., Mevorach, D., Tabib, A., Ortenberg, R., Markel, G., Miklić, K., ... Mandelboim, O. (2015). Binding of the Fap2 protein of fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity, 42(2), 344-355. https://doi.org/10.1016/j.immuni.2015.01.010

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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. 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.",

author = "Chamutal Gur and Yara Ibrahim and Batya Isaacson and Rachel Yamin and Jawad Abed and Moriya Gamliel and Jonatan Enk and Yotam Bar-On and Noah Stanietsky-Kaynan and Shunit Coppenhagen-Glazer and Noam Shussman and Gideon Almogy and Angelica Cuapio and Erhard Hofer and Dror Mevorach and Adi Tabib and Rona Ortenberg and Gal Markel and Karmela Mikli{\'c} and Stipan Jonjic and Brennan, {Caitlin A.} and Garrett, {Wendy S.} and Gilad Bachrach and Ofer Mandelboim",

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doi = "10.1016/j.immuni.2015.01.010",

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Gur, C, Ibrahim, Y, Isaacson, B, Yamin, R, Abed, J, Gamliel, M, Enk, J, Bar-On, Y, Stanietsky-Kaynan, N, Coppenhagen-Glazer, S, Shussman, N, Almogy, G, Cuapio, A, Hofer, E, Mevorach, D, Tabib, A, Ortenberg, R, Markel, G, Miklić, K, Jonjic, S, Brennan, CA, Garrett, WS, Bachrach, G & Mandelboim, O 2015, 'Binding of the Fap2 protein of fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack', Immunity, vol. 42, no. 2, pp. 344-355. https://doi.org/10.1016/j.immuni.2015.01.010

TY - JOUR

T1 - Binding of the Fap2 protein of fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack

AU - Gur, Chamutal

AU - Ibrahim, Yara

AU - Isaacson, Batya

AU - Yamin, Rachel

AU - Abed, Jawad

AU - Gamliel, Moriya

AU - Enk, Jonatan

AU - Bar-On, Yotam

AU - Stanietsky-Kaynan, Noah

AU - Coppenhagen-Glazer, Shunit

AU - Shussman, Noam

AU - Almogy, Gideon

AU - Cuapio, Angelica

AU - Hofer, Erhard

AU - Mevorach, Dror

AU - Tabib, Adi

AU - Ortenberg, Rona

AU - Markel, Gal

AU - Miklić, Karmela

AU - Jonjic, Stipan

AU - Brennan, Caitlin A.

AU - Garrett, Wendy S.

AU - Bachrach, Gilad

AU - Mandelboim, Ofer

PY - 2015/2/17

Y1 - 2015/2/17

N2 - 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.

AB - 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.

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U2 - 10.1016/j.immuni.2015.01.010

DO - 10.1016/j.immuni.2015.01.010

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C2 - 25680274

AN - SCOPUS:84923053706

SN - 1074-7613

VL - 42

SP - 344

EP - 355

JO - Immunity

JF - Immunity

IS - 2

ER -

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

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