Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.,Cell

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Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.
Cell ( IF 45.5 ) Pub Date : 2018-12-20 , DOI: 10.1016/j.cell.2018.11.010
Jun Wang ₁ , Miguel F Sanmamed ₁ , Ila Datar ₂ , Tina Tianjiao Su ₁ , Lan Ji ₁ , Jingwei Sun ₁ , Ling Chen ₃ , Yusheng Chen ₄ , Gefeng Zhu ₁ , Weiwei Yin ₅ , Linghua Zheng ₁ , Ting Zhou ₁ , Ti Badri ₁ , Sheng Yao ₁ , Shu Zhu ₁ , Agedi Boto ₆ , Mario Sznol ₇ , Ignacio Melero ₈ , Dario A A Vignali ₉ , Kurt Schalper ₂ , Lieping Chen ₁₀

Affiliation

Department of Immunobiology, Yale University, New Haven, CT 06511, USA.
Department of Pathology, Yale University, New Haven, CT 06510, USA.
Immunotherapy Institute, Fujian Medical University, Fuzhou, Fujian 350108, China.
Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350108, China.
Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, China.
Department of Immunobiology, Yale University, New Haven, CT 06511, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
Department of Medicine (Medical Oncology), Yale University, New Haven, CT 06510, USA.
Department of Immunology and Immunotherapy, University of Navarra, Pamplona 31008, Spain.
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
Department of Immunobiology, Yale University, New Haven, CT 06511, USA; Immunotherapy Institute, Fujian Medical University, Fuzhou, Fujian 350108, China; Department of Medicine (Medical Oncology), Yale University, New Haven, CT 06510, USA.

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.

中文翻译：

纤维蛋白原样蛋白1是LAG-3的主要免疫抑制配体。

淋巴细胞激活基因3（LAG-3）是一种免疫抑制受体，主要组织相容性复合体II类（MHC-II）作为规范配体。但是，是否MHC-II单独负责LAG-3的抑制功能仍存在争议。在这里，我们证明纤维蛋白原样蛋白1（FGL1），一种肝脏分泌的蛋白，是独立于MHC-II的主要LAG-3功能配体。FGL1抑制抗原特异性T细胞活化，而小鼠中FGL1的消融可促进T细胞免疫。单克隆抗体对FGL1-LAG-3相互作用的阻断可刺激肿瘤免疫力，并以受体-配体相互作用的方式治疗已建立的小鼠肿瘤。FGL1是人类癌细胞高度产生的，癌症患者血浆中的FGL1升高和预后不良以及对抗PD-1 / B7-H1治疗的耐药性相关。我们的发现揭示了一种免疫逃逸机制，对癌症免疫疗法的设计具有重要意义。

更新日期：2018-12-20

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