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Cell May 2024The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8 T cells, are important parameters for the control of tumor growth and response to...
The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8 T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Circadian Clocks; Circadian Rhythm; Endothelial Cells; Immune Checkpoint Inhibitors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Melanoma; Mice, Inbred C57BL; Tumor Microenvironment
PubMed: 38723627
DOI: 10.1016/j.cell.2024.04.015 -
PLoS Pathogens May 2024Circadian rhythms are intrinsic 24-hour oscillations found in nearly all life forms. They orchestrate key physiological and behavioral processes, allowing anticipation... (Review)
Review
Circadian rhythms are intrinsic 24-hour oscillations found in nearly all life forms. They orchestrate key physiological and behavioral processes, allowing anticipation and response to daily environmental changes. These rhythms manifest across entire organisms, in various organs, and through intricate molecular feedback loops that govern cellular oscillations. Recent studies describe circadian regulation of pathogens, including parasites, bacteria, viruses, and fungi, some of which have their own circadian rhythms while others are influenced by the rhythmic environment of hosts. Pathogens target specific tissues and organs within the host to optimize their replication. Diverse cellular compositions and the interplay among various cell types create unique microenvironments in different tissues, and distinctive organs have unique circadian biology. Hence, residing pathogens are exposed to cyclic conditions, which can profoundly impact host-pathogen interactions. This review explores the influence of circadian rhythms and mammalian tissue-specific interactions on the dynamics of pathogen-host relationships. Overall, this demonstrates the intricate interplay between the body's internal timekeeping system and its susceptibility to pathogens, which has implications for the future of infectious disease research and treatment.
Topics: Circadian Clocks; Animals; Host-Pathogen Interactions; Humans; Circadian Rhythm
PubMed: 38723104
DOI: 10.1371/journal.ppat.1012157 -
Circulation Research May 2024Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of... (Review)
Review
Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (I) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.
Topics: Humans; Animals; Heart Rate; Sinoatrial Node; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Biological Clocks
PubMed: 38723033
DOI: 10.1161/CIRCRESAHA.123.323250 -
Animal Cells and Systems 2024Biological rhythms play a crucial role in temporally regulating behavioral, physiological, and cellular processes within our bodies. One prominent example is the... (Review)
Review
Biological rhythms play a crucial role in temporally regulating behavioral, physiological, and cellular processes within our bodies. One prominent example is the circadian rhythm, which enables our bodies to anticipate external cues and regulate our internal processes accordingly. The circadian rhythm is controlled by a molecular feedback loop known as the circadian clock, present in nearly all cells. The regulation of genes involved in mitochondrial function is no exception. Key aspects such as oxidative phosphorylation, mitochondrial biogenesis, and mitochondrial morphology are regulated by the circadian clock. Functional changes in mitochondria can retrogradely affect the circadian rhythm. Furthermore, there are also transcriptional circadian clock-independent rhythms within mitochondria. This review discusses mitochondrial rhythms independently or in communication with the circadian clock in the nucleus at the cellular level.
PubMed: 38721230
DOI: 10.1080/19768354.2024.2347503 -
PloS One 2024The continued development in methylome analysis has enabled a more precise assessment of DNA methylation, but treatment of target tissue prior to analysis may affect DNA...
The continued development in methylome analysis has enabled a more precise assessment of DNA methylation, but treatment of target tissue prior to analysis may affect DNA analysis. Prediction of age based on methylation levels in the genome (DNAmAge) has gained much interest in disease predisposition (biological age estimation), but also in chronological donor age estimation in crime case samples. Various epigenetic clocks were designed to predict the age. However, it remains unknown how the storage of the tissues affects the DNAmAge estimation. In this study, we investigated the storage method impact of DNAmAge by the comparing the DNAmAge of the two commonly used storage methods, freezing and formalin-fixation and paraffin-embedding (FFPE) to DNAmAge of fresh tissue. This was carried out by comparing paired heart tissue samples of fresh tissue, samples stored by freezing and FFPE to chronological age and whole blood samples from the same individuals. Illumina EPIC beadchip array was used for methylation analysis and the DNAmAge was evaluated with the following epigenetic clocks: Horvath, Hannum, Levine, Horvath skin+blood clock (Horvath2), PedBE, Wu, BLUP, EN, and TL. We observed differences in DNAmAge among the storage conditions. FFPE samples showed a lower DNAmAge compared to that of frozen and fresh samples. Additionally, the DNAmAge of the heart tissue was lower than that of the whole blood and the chronological age. This highlights caution when evaluating DNAmAge for FFPE samples as the results were underestimated compared with fresh and frozen tissue samples. Furthermore, the study also emphasizes the need for a DNAmAge model based on heart tissue samples for an accurate age estimation.
Topics: Humans; DNA Methylation; Paraffin Embedding; Formaldehyde; Myocardium; Tissue Fixation; Male; Adult; Female; Middle Aged; Cryopreservation; Adolescent; Aged; Young Adult
PubMed: 38718072
DOI: 10.1371/journal.pone.0299557 -
Cell Reports May 2024Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely...
Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow ILCPs.
Topics: Animals; Mice; Circadian Clocks; Cytokines; Mice, Inbred C57BL; Bone Marrow; Signal Transduction; Receptors, CXCR4; Bone Marrow Cells; Lymphoid Progenitor Cells; Immunity, Innate; Cell Movement; Nuclear Receptor Subfamily 1, Group F, Member 1; Receptors, Glucocorticoid; Lymphocytes
PubMed: 38717905
DOI: 10.1016/j.celrep.2024.114200 -
ELife May 2024Studies of the starlet sea anemone provide important insights into the early evolution of the circadian clock in animals.
Studies of the starlet sea anemone provide important insights into the early evolution of the circadian clock in animals.
Topics: Animals; Biological Evolution; Circadian Clocks; Circadian Rhythm; Cnidaria; Sea Anemones
PubMed: 38716806
DOI: 10.7554/eLife.98512 -
JCI Insight May 2024Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed...
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.
Topics: Humans; Pancreatic Neoplasms; Transcriptome; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Circadian Rhythm; Organoids; Circadian Clocks; Antineoplastic Agents; Adenocarcinoma; Chronotherapy
PubMed: 38716727
DOI: 10.1172/jci.insight.177697 -
Nature Communications May 2024As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time...
As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's performance in adding timestamps to both bulk and single-cell transcriptomic samples collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNAseq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNAseq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.
Topics: Single-Cell Analysis; Animals; Mice; Circadian Rhythm; Transcriptome; Circadian Clocks; Humans; Gene Expression Profiling; Computational Biology; Skin; Software; Fibroblasts; Sequence Analysis, RNA
PubMed: 38714698
DOI: 10.1038/s41467-024-48041-6 -
BioRxiv : the Preprint Server For... Apr 2024Cooperation between the circadian transcription factor (TF) CLOCK:BMAL1 and other TFs at -regulatory elements (CREs) is critical to daily rhythms of transcription. Yet,...
Cooperation between the circadian transcription factor (TF) CLOCK:BMAL1 and other TFs at -regulatory elements (CREs) is critical to daily rhythms of transcription. Yet, the modalities of this cooperation are unclear. Here, we analyzed the co-binding of multiple TFs on single DNA molecules in mouse liver using single molecule footprinting (SMF). We found that SMF reads clustered in stereotypic chromatin states that reflect distinguishable organization of TFs and nucleosomes, and that were remarkably conserved between all samples. DNA protection at CLOCK:BMAL1 binding motif (E-box) varied between CREs, from E-boxes being solely bound by CLOCK:BMAL1 to situations where other TFs competed with CLOCK:BMAL1 for E-box binding. SMF also uncovered CLOCK:BMAL1 cooperative binding at E-boxes separated by 250 bp, which structurally altered the CLOCK:BMAL1-DNA interface. Importantly, we discovered multiple nucleosomes with E-boxes at entry/exit sites that were removed upon CLOCK:BMAL1 DNA binding, thereby promoting the formation of open chromatin states that facilitate DNA binding of other TFs and that were associated with rhythmic transcription. These results demonstrate the utility of SMF for studying how CLOCK:BMAL1 and other TFs regulate stereotypical chromatin states at CREs to promote transcription.
PubMed: 38712031
DOI: 10.1101/2024.04.24.590818