具核梭杆菌的Fap2蛋白与人抑制性受体TIGIT的结合可保护肿瘤免受免疫细胞攻击。
Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.
作者信息
Gur Chamutal, Ibrahim Yara, Isaacson Batya, Yamin Rachel, Abed Jawad, Gamliel Moriya, Enk Jonatan, Bar-On Yotam, Stanietsky-Kaynan Noah, Coppenhagen-Glazer Shunit, Shussman Noam, Almogy Gideon, Cuapio Angelica, Hofer Erhard, Mevorach Dror, Tabib Adi, Ortenberg Rona, Markel Gal, Miklić Karmela, Jonjic Stipan, Brennan Caitlin A, Garrett Wendy S, Bachrach Gilad, Mandelboim Ofer
机构信息
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.
The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, 91120, Israel.
出版信息
Immunity. 2015 Feb 17;42(2):344-355. doi: 10.1016/j.immuni.2015.01.010. Epub 2015 Feb 10.
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.
诸如具核梭杆菌之类的细菌存在于肿瘤微环境中。然而，肿瘤内细菌的免疫后果仍不清楚。在此，我们已经表明，在各种具核梭杆菌菌株存在的情况下，自然杀伤（NK）细胞对各种肿瘤的杀伤作用受到抑制。我们的数据支持这种具核梭杆菌介导的抑制作用是由人类而非小鼠的TIGIT介导的，TIGIT是一种存在于所有人类NK细胞和各种T细胞上的抑制性受体。使用具核梭杆菌突变体文库，我们发现具核梭杆菌的Fap2蛋白直接与TIGIT相互作用，导致NK细胞细胞毒性受到抑制。我们进一步证明，肿瘤浸润淋巴细胞表达TIGIT，并且具核梭杆菌通过Fap2也抑制T细胞活性。我们的结果确定了一种细菌依赖性的肿瘤免疫逃逸机制，其中肿瘤利用具核梭杆菌的Fap2蛋白通过TIGIT抑制免疫细胞活性。
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