Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion
Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion
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泛癌症分析揭示昼夜节律紊乱与 T 细胞耗竭相关。
DOI：
10.3389/fimmu.2019.02451
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发表时间：
2019-10-24
影响因子：
7.3
通讯作者：
Mao, Renfang
中科院分区：
文献类型：
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作者：
Wu, Yingcheng;Tao, Baorui;Mao, Renfang
虽然生物钟功能失调已经成为癌症的标志，但我们对相关机制的理解仍然存在根本性的差距。在这里，我们系统地分析了生物钟的核心基因（CLOCK，ARNTL，ARNTL 2，NPAS 2，NR 1D 1，NR 1D 2，ARN 1，ARN 2，RORA，RORB，RORC，PER 1，PER 2和PER 3）在广泛的癌症。令我们惊讶的是，核心负调节因子（PER 1，PER 2，PER 3，PER 1和PER 2）始终下调，而核心正调节因子显示出最小的变化，表明癌症中的昼夜节律钟被破坏。这种下调源于拷贝数变异，其中杂合缺失占主导地位。生物钟紊乱与患者预后显著相关。进一步的途径富集分析表明，生物钟广泛影响45条途径，如Ras信号通路和T细胞受体信号通路。通过使用最先进的免疫细胞去卷积和途径定量，我们证明了异常的生物钟有助于T细胞耗竭和免疫抑制分子如PD-L1和CTLA-4的整体上调。总之，生物钟的节奏在癌症中被打乱。与免疫逃避相关的异常生物钟可能是癌症的潜在标志。
Although dysfunctional circadian clock has emerged as a hallmark of cancer, fundamental gaps remain in our understanding of the underlying mechanisms involved. Here, we systematically analyze the core genes of the circadian clock (CLOCK, ARNTL, ARNTL2, NPAS2, NR1D1, NR1D2, CRY1, CRY2, RORA, RORB, RORC, PER1, PER2, and PER3) across a broad range of cancers. To our surprise, core negative regulators (PER1, PER2, PER3, CRY1, and CRY2) are consistently downregulated, while core positive regulators show minimal alterations, indicating disrupted circadian clock in cancers. Such downregulation originates from copy number variations where heterozygous deletion predominates. The disrupted circadian clock is significantly associated with patient outcome. Further pathway enrichment analysis suggests that the circadian clock widely impacts 45 pathways such as the Ras signaling pathway and T cell receptor signaling pathway. By using state-of-the-art immune cell deconvolution and pathway quantification, we demonstrate that abnormal circadian clock contributes to T cell exhaustion and global upregulation of immune inhibitory molecules such as PD-L1 and CTLA-4. In summary, the rhythm of the circadian clock is disrupted in cancers. Abnormal circadian clock linked with immune evasion may serve as a potential hallmark of cancer.