Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion

Abstract

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.

Immunological analysis and differential genes screening of venous thromboembolism

“…At present, most of the research on CD3G focuses on tumors, and there are few reports on vascular diseases and thrombosis. NR1D2, a nuclear hormone receptor gene, is associated with circadian rhythm, and circadian dysregulation widely affects Ras signaling pathways, T cell receptor signaling pathways, and then triggers various diseases such as tumors [ 40 ]. NR1D2 is also an important regulator of vascular inflammation and is related to the occurrence of cardiovascular events [ 41 ].…”

Stromal Expression of the Core Clock Gene Period 2 Is Essential for Tumor Initiation and Metastatic Colonization

“…The circadian clock is a major regulator of metabolism and cell cycle and its disruption is well known to promote cancer. In cancer cells, both PER1 and PER2 were shown to act as tumor suppressors ( Fu et al, 2002 , 2016 ; Yang et al, 2009 ; Su et al, 2017 ; Zhu et al, 2019 ; Hou et al, 2020 ; Liu et al, 2020 ) and mutations in these genes were associated with human cancer ( Chen et al, 2005 ; Kettner et al, 2014 ; Wu et al, 2019 ). However, whether these effects are clock-dependent is not clear.…”

Immunological Analysis and Differential Genes Screening of Venous Thromboembolism

“…At present, most of the research on CD3G focuses on tumors, and there are few reports on vascular diseases and thrombosis. NR1D2, a nuclear hormone receptor gene, is associated with circadian rhythm, and circadian dysregulation widely affects Ras signaling pathways, T cell receptor signaling pathways, and then triggers various diseases such as tumors [34] . NR1D2 is also an important regulator of vascular in ammation and is related to the occurrence of cardiovascular events [35] .…”