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首页> 外文期刊>The Journal of Experomental Medicine >The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment
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The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment

机译：EGR2靶向LAG-3和4-1BB描述和调节肿瘤微环境中功能异常的抗原特异性CD8 + T细胞

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Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous antitumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms, but also a T cell–intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining tumor-specific dysfunctional TILs, and PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro. In this study, we show that the Egr2-driven cell surface proteins LAG-3 and 4-1BB can identify dysfunctional tumor antigen–specific CD8+ TIL. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+ TILs, but not in lymphoid organs. Functional analysis revealed defective IL-2 and TNF production yet retained expression of IFN-γ and regulatory T cell–recruiting chemokines. Transcriptional and phenotypic characterization revealed coexpression of multiple additional co-stimulatory and co-inhibitory receptors. Administration of anti–LAG-3 plus anti–4-1BB mAbs was therapeutic against tumors in vivo, which correlated with phenotypic normalization. Our results indicate that coexpression of LAG-3 and 4-1BB characterize dysfunctional T cells within tumors, and that targeting these receptors has therapeutic utility.
机译：尽管肿瘤浸润淋巴细胞（TIL）的存在表明内源性抗肿瘤反应，但免疫调节途径可以破坏效应物相并使肿瘤逃逸。负调控途径包括外在抑制机制，也包括T细胞内在功能障碍状态。缺少定义肿瘤特异性功能障碍性TIL的细胞表面标志物阻碍了更详细的研究，仅PD-1是不够的。最近，我们发现转录因子Egr2是控制体外无氧状态的关键组成部分。在这项研究中，我们表明Egr2驱动的细胞表面蛋白LAG-3和4-1BB可以识别功能异常的肿瘤抗原特异性CD8 + TIL。在大多数CD8 + TILs上观察到4-1BB和LAG-3的共表达，但在淋巴器官中却没有。功能分析表明，IL-2和TNF产生缺陷，但仍保留IFN-γ和调节性T细胞趋化因子的表达。转录和表型表征揭示了多种其他共刺激和共抑制受体的共表达。抗LAG-3加上抗4-1BB mAb的给药对体内肿瘤具有治疗作用，这与表型正常化有关。我们的结果表明，LAG-3和4-1BB的共表达是肿瘤内功能失调的T细胞的特征，靶向这些受体具有治疗作用。

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