Department of Medicine, The University of Chicago, 924 E. 57th St. JFK-R312, Chicago, IL 60637 USA.
Genentech, Inc., 1 DNA Way MS: 245c, South San Francisco, CA 94080 USA.
J Immunother Cancer. 2015 Jan 20;3(1):1. doi: 10.1186/s40425-014-0045-x. eCollection 2015.
T cells have the capacity to eliminate tumors but the signaling pathways by which they do so are incompletely understood. T cell priming requires activation of the transcription factors AP-1, NFAT and NF-κB downstream of the TCR, but whether activation of T cell-NF-κB in vivo is required for tumor control has not been addressed. In humans and mice with progressively growing tumors, the activity of T cell-intrinsic NF-κB is often reduced. However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth. T cell-NF-κB is important for T cell survival and effector differentiation and plays an important role in enabling T cells to reject cardiac and islet allografts, suggesting the possibility that it may also be required for tumor elimination. In this study, we tested whether normal T cell-NF-κB activation is necessary for the rejection of tumors whose growth is normally controlled by the immune system.
Mice with genetically impaired T cell-NF-κB activity were subcutaneously injected with MC57-SIY tumor cells. Tumor growth was measured over time, and the anti-tumor immune response was evaluated using flow cytometry and cytokine detection assays.
Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells.
Our results have identified the NF-κB pathway as an important signaling axis in T cells, required for the elimination of growing tumors in vivo. Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.
T 细胞具有消除肿瘤的能力，但它们的信号通路尚不完全清楚。T 细胞的初始激活需要 TCR 下游的转录因子 AP-1、NFAT 和 NF-κB 的激活，但 T 细胞-NF-κB 的体内激活是否需要控制肿瘤尚未得到解决。在患有逐渐生长的肿瘤的人类和小鼠中，T 细胞固有 NF-κB 的活性通常降低。然而，尚不清楚这是否是无法排斥转化细胞的原因，还是肿瘤生长的结果。T 细胞-NF-κB 对于 T 细胞的存活和效应器分化很重要，并且在使 T 细胞排斥心脏和胰岛同种异体移植物方面发挥着重要作用，这表明它可能也需要肿瘤的消除。在这项研究中，我们测试了正常 T 细胞-NF-κB 激活是否是排斥其生长通常受免疫系统控制的肿瘤所必需的。
用遗传缺陷的 T 细胞-NF-κB 活性的小鼠皮下注射 MC57-SIY 肿瘤细胞。随着时间的推移测量肿瘤生长，并通过流式细胞术和细胞因子检测分析评估抗肿瘤免疫反应。
尽管具有相同数量的肿瘤反应性 T 细胞积累，但是缺乏 T 细胞-NF-κB 活性的小鼠无法排斥肿瘤。此外，TCR 下游 NF-κB 信号的特异性损害足以防止肿瘤排斥。缺乏 T 细胞-NF-κB 的小鼠的肿瘤抗原特异性 T 细胞 IFN-γ 和 TNF-α产生以及细胞毒性能力均降低，这表明该转录因子在肿瘤特异性效应 T 细胞的效应分化中起重要作用。
我们的结果确定了 NF-κB 途径是 T 细胞中重要的信号轴，需要在体内消除生长中的肿瘤。维持或增强 T 细胞-NF-κB 活性可能是抗肿瘤免疫治疗的一种有前途的方法。
Zotero 插件
