Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 559 records · Page 31Linked to original sources

bioRxiv2020

Concerted action of kinesin-1 KIF5B and kinesin-3 KIF13B promotes efficient transport of exocytotic vesicles to microtubule plus ends

Intracellular transport relies on multiple kinesins, but it is poorly understood which kinesins are present on particular cargos, what their contributions are and whether they act simultaneously on the same cargo. Here, we show that Rab6-positive secretory vesicles are transported from the Golgi apparatus to the cell periphery by kinesin-1 KIF5B and kinesin-3 KIF13B, which determine the location of secretion events. KIF5B plays a dominant role, whereas KIF13B helps Rab6 vesicles to reach freshly polymerized microtubule ends, to which KIF5B binds poorly, likely because its cofactors, MAP7-family proteins, are slow in populating these ends. Sub-pixel localization demonstrated that during microtubule plus-end directed transport, both kinesins localize to the vesicle front and can be engaged on the same vesicle. When vesicles reverse direction, KIF13B relocates to the middle of the vesicle, while KIF5B shifts to the back, suggesting that KIF5B but not KIF13B undergoes a tug-of-war with a minus-end directed motor.

cell biology↗

bioRxiv2020

The Janus-faced role of KDM5B heterogeneity in melanoma: differentiation as a situational driver of both growth arrest and drug-resistance

Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. For example, melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a new dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor growth and plasticity and primes melanoma cells towards lineage-specific elimination.

cancer biology↗

bioRxiv2020

Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase (DHODH) as its target, along with the discovery that knockdown of genes in pyrimidine salvage pathways sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was efficiently converted into its triphosphates in cells. When combined with GSK983, it led to large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral genome infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activities of RdRp inhibitors.

biochemistry↗

bioRxiv2020

Neural Correlates of Positive and Negative Valence System Dysfunction in Adolescents Revealed by Data-Driven Parcellation and Resting-State Network Modeling

ObjectiveAdolescence is a period of rapid brain development when symptoms of mood, anxiety, and other disorders often first emerge, suggesting disruptions in maturing reward circuitry may play a role in mental illness onset. Here, we characterized associations between resting-state network properties and psychiatric symptomatology in medication-free adolescents with a wide range of symptom severity. MethodsAdolescents (age 12-20) with mood and/or anxiety symptoms (n=68) and healthy controls (n=19) completed diagnostic interviews, depression/anhedonia/anxiety questionnaires, and 3T resting-state fMRI (10min/2.3mm/TR=1s). Data were preprocessed (HCP Pipelines), aligned (MSMAll), and parcellated into 750 nodes encompassing the entire cortex/subcortex (Cole-Anticevic Brain-wide Network Partition). Weighted graph theoretical metrics (Strength Centrality=CStr; Eigenvector Centrality=CEig; Local Efficiency=ELoc) were estimated within Whole Brain and task-derived Reward Anticipation/Attainment/Prediction Error networks. Associations with clinical status and symptoms were assessed non-parametrically (two-tailed pFWE<0.05). ResultsRelative to controls, clinical adolescents had increased ventral striatum CEig within the Reward Attainment network. Across subjects, depression correlated with subgenual cingulate CStr and ELoc, anhedonia correlated with ventromedial prefrontal CStr and lateral amygdala ELoc, and anxiety negatively correlated with parietal operculum CEig and medial amygdala ELoc within the Whole Brain network. ConclusionsUsing a data-driven analysis approach, high-quality parcellation, and clinically diverse adolescent cohort, we found that symptoms within positive and negative valence system constructs differentially associated with resting-state network abnormalities: depression and anhedonia, as well as clinical status, involved greater influence and communication efficiency in prefrontal and limbic reward areas, whereas anxiety was linked to reduced influence/efficiency in amygdala and cortical regions involved in stimulus monitoring.

neuroscience↗

bioRxiv2020

Small Molecule Modulation of Microbiome Ecosystem: A Systems Pharmacology Perspective

An increasing body of evidence suggests that microbes are not only strongly associated with many human diseases but also responsible for the efficacy, resistance, and toxicity of drugs. Small-molecule drugs which can precisely fine-tune the microbial ecosystem on the basis of individual patients may revolutionize biomedicine. However, emerging endeavors in small-molecule microbiome drug discovery continue to follow a conventional "one-drug-one-target-one-disease" process. It is often insufficient and less successful in tackling complex systematic diseases. A systematic pharmacology approach that intervenes multiple interacting pathogenic species in the microbiome, could offer an attractive alternative solution. Advances in the Human Microbiome Project have provided numerous genomics data to study microbial interactions in the complex microbiome community. Integrating microbiome data with chemical genomics and other biological information enables us to delineate the landscape for the small molecule modulation of the human microbiome network. In this paper, we construct a disease-centric signed microbe-microbe interaction network using metabolite information of microbes and curated microbe effects on human health from published work. We develop a Signed Random Walk with Restart algorithm for the accurate prediction of pathogenic and commensal species. With a survey on the druggable and evolutionary space of microbe proteins, we find that 8-10% of them can be targeted by existing drugs or drug-like chemicals and that 25% of them have homologs to human proteins. We also demonstrate that drugs for diabetes are enriched in the potential inhibitors that target pathogenic microbe without affecting the commensal microbe, thus can be repurposed to modulate the microbiome ecosystem. We further show that periplasmic and cellular outer membrane proteins are overrepresented in the potential drug targets set in pathogenic microbe, but not in the commensal microbe. The systematic studies of polypharmacological landscape of the microbiome network may open a new avenue for the small-molecule drug discovery of microbiome. Author SummaryAs one of the most abundant components in human bodies, the microbiome has an extensive impact on human health. Pathogenic-microbes have become emerging potential therapeutic targets. Small-molecule drugs that only intervene in the growth of a specific pathogenic microbe without considering the interacting dynamics of the microbiome community may disrupt the ecosystem homeostasis, thus can cause drug side effect or prompt drug resistance. To discover novel drugs for safe and effective microbe-targeting therapeutics, a systematic approach is needed to fine-tune the microbiome ecosystem. To this end, we built a disease-centric signed microbe-microbe interaction network which accurately predicts the pathogenic or commensal effect of microbe on human health. Based on annotated and predicted pathogens and commensal species, we performed a systematic survey on therapeutic space and target landscape of existing drugs for modulating the microbiome ecosystem. Enrichment analysis on potential microbe-targeting drugs shows that drugs for diabetes could be repurposed to maintain the healthy state of microbiome. Furthermore, periplasmic and cellular outer membrane proteins are overrepresented in the potential drug targets of pathogenic-microbes, but not in proteins that perturb commensal-microbes. Our study may open a new avenue for the small molecule drug discovery of microbiome.

bioinformatics↗

bioRxiv2020

In Vivo Efficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models

KBP-7072 is a novel aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative multidrug resistant bacterial isolates and strains. Antibacterial activity and the PK/PD relationship were assessed using in vivo infection models. Six to 8-week-old female CD-1 mice were randomized to oral KBP-7072, minocycline and vehicle in a Klebsiella pneumoniae murine model, and KBP-7072, linezolid and vehicle for a Streptococcus pneumoniae murine model. Each animal was inoculated with K. pneumoniae or S. pneumoniae placed on the tip of the nares. KBP-7072 and antibiotics were started 3 hours post inoculation and continued for 3 days for K. pneumoniae, and were started 18 hours post inoculation and continued for 3 days for S. pneumoniae. Animals were euthanized at 0 (control group), 24, 48 or 72 hours post final dose. In vivo efficacy and PK/PD parameters were determined in Staphylococcus aureus isolate (6424MRSA-363), K. pneumoniae isolate (6680kpn-522), and E. coli isolate (6691eco-558) murine thigh infection models. In vivo efficacy and PK/PD parameters (fAUC/MIC, fCmax/MIC and %T>MICfree) were calculated. Respiratory infection occurred in all inoculated mice. KBP-7072 produced a significant (p<0.05 to <0.001) dose-dependent decrease in colony forming units (CFUs) at all doses and a dose-dependent increase in survival rate (p<0.001 vs. vehicle). The median survival in all KBP-7072-treated groups was significantly greater vs. comparators (p<0.001). These results demonstrate potent in vivo efficacy for KBP-7072 and determined that the AUC/MIC parameter was optimal for assessing bacteriostatic and bactericidal effects of KBP-7072.

pharmacology and toxicology↗

bioRxiv2020

The effects of human umbilical cord mesenchymal stem cell transplantation on female fertility preservation in mice

Female fertility is the capacity to produce oocytes and achieve fertilization and pregnancy, and these outcomes are impaired by age, diseases, environment and social pressure. However, there is no effective therapy that preserves female reproductive ability. Mesenchymal stromal cells (MSCs) can exhibit multidirectional differentiation potential, and they have gained great attention as a tool for preserving female fertility. Therefore, this study uses human umbilical cords-MSCs (Huc-MSCs) to preserve and restore fertility in aging female mice and chemotherapy-damaged mice through the rescue of ovarian function and the reconstruction of the fallopian tubes and uterus. In our study, 2 mouse models were generated: aging mice (37 weeks old) and chemotherapy-damaged mice. Then, we injected Huc-MSCs into mice through the tail vein. After treatment, the effect of MSCs on the ovary, fallopian tubes and uterus was evaluated by analyzing gonadal hormone levels and by performing morphological analysis and statistical analysis. The levels of E2 and FSH exhibited a significant recovery after HUC-MSC transplantation both in aging mice and mice treated with chemotherapy. Huc-MSC treatment also increased the numbers of primordial, developing and preovulatory follicles in the ovaries of mice. Meanwhile, MSCs have been shown to rescue the morphology of the fallopian tubes and uterus through mechanisms such as regenerating the cilia in fallopian tubes and reforming glands and chorionic villi in the uterus. Therefore, it is suggested that Huc-MSCs may represent an effective potential treatment for preserving female fertility through recovery from chemotherapy damage and rescuing female reproductive organs from the effects of aging.

cell biology↗

bioRxiv2020

A Self-Supervised Workflow for Particle Picking in Cryo-EM

High-resolution single-particle cryo-EM data analysis relies on accurate particle picking. To facilitate the particle picking process, we have developed a self-supervised workflow. Our workflow includes an iterative strategy to use the 2D class average to improve training particles and a progressively improved convolutional neural network (CNN) for particle picking. To automate the selection of particles, we define a threshold (%/Res) using the ratio of percentage class distribution and resolution as a cutoff. Our workflow has been tested using six publicly available data sets with different particle sizes and shapes, and is able to automatically pick particles with minimal user input. The picked particles support high-resolution reconstructions at 3.0 [A] or better. Our workflow offers a way toward automated single-particle Cryo-EM data analysis at the stage of particle picking. The workflow may be used in conjunction with commonly used single-particle analysis packages such as Relion, cryoSPARC, cisTEM, SPHIRE, and EMAN2.

biochemistry↗

bioRxiv2020

A Clock-Driven Neural Network Critical for Arousal

The daily cycling of sleep and arousal states is among the most prominent biological rhythms under circadian control. While much is known about the core circadian clock1,2, how this clock tunes sleep and arousal remains poorly understood3. In Drosophila, we previously characterized WIDE AWAKE (WAKE), a clock-output molecule that promotes sleep at night4,5. Here, we show that the function of WAKE in regulating circadian-dependent neural excitability and arousal is conserved in mice. mWake+ cells are found in the suprachiasmatic nucleus (SCN) and dorsomedial hypothalamus (DMH). mWakeDMH neurons drive wakefulness and exhibit rhythmic spiking, with greater firing during the night vs the day. Loss of mWAKE leads to increased spiking of mWake+ SCN and DMH neurons and prominent behavioural arousal, specifically during the night. Single-cell sequencing, imaging, and patch-clamp experiments reveal that mWakeDMH neurons constitute a glutamatergic/GABAergic population that projects widely, receives neuromodulatory input, and acts on neuromodulatory neurons. Strikingly, broad chemogenetic silencing of mWake+ cells leads to profound loss of behavioural responsiveness and low amplitude, low frequency electroencephalography waveforms. These findings suggest that the genetic mechanisms regulating circadian control of sleep and arousal are conserved across >500 million years of evolution and define a clock-regulated neural network critical for arousal.

neuroscience↗

bioRxiv2020

Structural Basis for Ca2+-Dependent Activation of a Plant Metacaspase

Plants metacaspases mediate programmed cell death in development 1,2, biotic and abiotic stresses 3, damage-induced immune response 4, and resistance to pathogen attack 5. Most metacaspases require Ca2+ for their activation and substrate processing 6-8. However, the Ca2+-dependent activation mechanism remains elusive 9-11. Here we report the crystal structure of Metacaspase 4 from Arabidopsis thaliana (AtMC4) that modulates Ca2+-dependent, damage-induced plant immune defense. The AtMC4 structure exhibits an inhibitory conformation in which a large linker domain blocks activation and substrate access. In addition, the side chain of Lys225 in the linker domain blocks the active site by sitting directly between two catalytic residues. We show that the activation of AtMC4 and cleavage of its physiological substrate involve multiple cleavages in the linker domain upon activation by Ca2+. Our analysis provides insight into the Ca2+-dependent activation of AtMC4 and lays the basis for tuning its activity in response to stresses that may help engineer more sustainable crops for production of food and biofuel.

biochemistry↗

bioRxiv2020

Honey bee suppresses the parasitic mite Vitellogenin by antimicrobial peptide

The negative effects of honey bee parasitic mites and deformed wing virus (DWV) on honey bee and colony health have been well characterized. However, the relationship between DWV and mites, particularly viral replication inside the mites, remains unclear. Furthermore, the physiological outcomes of honey bee immune responses stimulated by DWV and the mite to the host (honey bee) and perhaps the pathogen/parasite (DWV/mite) are not yet understood. To answer these questions, we studied the tripartite interactions between the honey bee, Tropilaelaps mercedesae, and DWV as the model. T. mercedesae functioned as a vector for DWV without supporting active viral replication. Thus, DWV negligibly affected mite fitness. Mite infestation induced mRNA expression of antimicrobial peptides (AMPs), Defensin-1 and Hymenoptaecin, which correlated with DWV copy number in honey bee pupae and mite feeding, respectively. Feeding T. mercedesae with fruit fly S2 cells heterologously expressing honey bee Hymenoptaecin significantly downregulated mite Vitellogenin expression, indicating that the honey bee AMP manipulates mite reproduction upon feeding on bee. Our results provide insights into the mechanism of DWV transmission by the honey bee parasitic mite to the host, and the novel role of AMP in defending against mite infestation.

microbiology↗

bioRxiv2020

FL-QSAR: a federated learning based QSAR prototype for collaborative drug discovery

MotivationQuantitative structure-activity relationship (QSAR) analysis is commonly used in drug discovery. Collaborations among pharmaceutical institutions can lead to a better performance in QSAR prediction, however, intellectual property and related financial interests remain substantially hindering inter-institutional collaborations in QSAR modeling for drug discovery. ResultsFor the first time, we verified the feasibility of applying the horizontal federated learning (HFL), which is a recently developed collaborative and privacy-preserving learning framework to perform QSAR analysis. A prototype platform of federated-learning-based QSAR modeling for collaborative drug discovery, i.e, FL-QSAR, is presented accordingly. We first compared the HFL framework with a classic privacy-preserving computation framework, i.e., secure multiparty computation (MPC) to indicate its difference from various perspective. Then we compared FL-QSAR with the public collaboration in terms of QSAR modeling. Our extensive experiments demonstrated that (1) collaboration by FL-QSAR outperforms a single client using only its private data, and (2) collaboration by FL-QSAR achieves almost the same performance as that of collaboration via cleartext learning algorithms using all shared information. Taking together, our results indicate that FL-QSAR under the HFL framework provides an efficient solution to break the barriers between pharmaceutical institutions in QSAR modeling, therefore promote the development of collaborative and privacy-preserving drug discovery with extendable ability to other privacy-related biomedical areas. Availability and implementationThe source codes of the federated learning simulation and FL-QSAR are available on the GitHub: https://github.com/bm2-lab/FL-QSAR

bioinformatics↗

bioRxiv2020

Lack of dcf1 leads to neuronal migration delay, axonal swollen and autism-related deficits

Perturbed neuronal migration and abnormal axonogenesis have been shown to be implicated in the pathogenesis of autism spectrum disorder (ASD). However, the molecular mechanism remains unknown. Here we demonstrate that dendritic cell factor 1(DCF1) is involved in neuronal migration and axonogenesis. The deletion of dcf1 in mice delays the localization of callosal projection neurons, while dcf1 overexpression restores normal migration. Delayed neurons appear as axon swelling and axonal boutons loss, resulting in a permanent deficit in the callosal projections. Western blot analysis indicates that absence of dcf1 leads to the abnormal activation of ERK signal. Differential protein expression assay shows that PEBP1, a negative regulator of the ERK signal, is significant downregulation in dcf1 KO mice. Direct interaction between DCF1 and PEBP1 is confirmed by Co-immunoprecipitation test, thus indicating that DCF1 regulates the ERK signal in a PEBP1-dependent pattern. As a result of the neurodevelopmental migration disorder, dcf1 deletion results in ASD-like behaviors in mice. This finding identifies a link between abnormal activated ERK signaling, delayed neuronal migration and autistic-like behaviors in humans.

neuroscience↗

bioRxiv2020

Integrated decoding hematopoiesis and leukemogenesis at single-cell resolution and its clinical implication

Integrated analyses of hematopoiesis and leukemogenesis could provide new biological and clinical insights1,2. Here we constructed a comprehensive cell atlas using [~]100,000 single cell transcriptomes of bone marrow mononuclear cells and its subsets from 5 healthy samples and 13 leukemia samples. Trajectory analysis showed hematopoietic stem cells continuously differentiated through tree-like structure into 7 lineages. Although our single cell analyses showed the major cellular heterogeneity were inter-patients, there were distinct leukemia cell subpopulations within patient. We developed counterpart composite index (CCI) for projecting leukemia cell subpopulation into reference hematopoietic cells, to identify their healthy counterparts that could predict leukemia subtype and clinical outcome. Interestingly, we found the trajectories of leukemogenesis were similar to that of their healthy counterparts, indicating lineage relationship of leukemia cell subpopulations. Single cell analyses of leukemia patient at diagnosis, refractory, remission and relapse vividly presented dynamics of cell population and the underlying genes. Single cell transcriptomic variants analyses showed the relapsed leukemia cells, whose healthy counterparts were closer to the root of hematopoietic tree, were derived from an early minor leukemia cell population. This study not only increased our understanding of hematopoiesis and leukemogenesis, but also provided an approach for leukemia classification and clinical outcome prediction.

genomics↗

bioRxiv2020

Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser

The Pro47Ser variant of p53 exists in African-descent populations, and is associated with increased cancer risk in humans and mice. This variant, hereafter S47, shows altered regulation of the cystine importer Slc7a11, and S47 cells possess increased cysteine and glutathione (GSH) accumulation compared to cells with wild type p53. In this study we show that mice containing the S47 variant have increased mTOR activity, increased oxidative metabolism, larger size, and improved metabolic efficiency. Mechanistically, we show that there is increased association between mTOR and its positive regulator Rheb in S47 cells, due to altered redox state of GAPDH, which normally binds and sequesters Rheb. Compounds that decrease glutathione in S47 cells normalize GAPDH-Rheb complex formation and mTOR activity. The enhanced metabolic efficiency may have been selected for in early Africa, making the S47 variant one of a growing number of cancer-predisposing genetic variants that possesses other positive, potentially selectable attributes.

cancer biology↗

bioRxiv2020

Exon 13-skipped USH2A protein retains functional integrity in mice, suggesting an exon skipping therapeutic approach to treat USH2A-associated disease.

Mutations in the USH2A gene are the most common cause of non-syndromic inherited retinal degeneration and Usher syndrome, which is characterized by congenital deafness and progressive vision loss. Development of a vector mediated therapy for USH2A-associated disease has been challenging due to its large size of coding sequence (~15.6kb). Therefore, there is an unmet need to develop alternative therapeutic strategies. The USH2A protein (Usherin) contains many repetitive domains, and it has been hypothesized that some domains may be dispensable with regard to protein function. Here, we show that skipping of exon 13 of the human USH2A gene or the equivalent exon 12 of the mouse Ush2a gene results in an in-frame transcript that produces functional Usherin protein. This nearly full length Usherin rescues the ciliogenesis in Ush2a null cells as well as the cochlear and retinal phenotypes in Ush2a null mice. Together, our results support the development of exon-skipping strategies to treat both visual and hearing loss in patients with USH2A-associated disease due to mutations in exon 13.

molecular biology↗

bioRxiv2020

A variant in SMOC2, inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

Previously study showed that SMOC, a matricellular protein, inhibits BMP signaling downstream of its receptor via activation of mitogen-activated protein kinase (MAPK) signaling. In our study, exome sequencing revealed a missense mutation (c.1076T>G, p.Leu359Arg) in EC domain of SMOC2 in a Chinese family with multiple epiphyseal disease (MED). The pathogenicity of this SMOC2 variant was verified by Smoc2L359R/L359R knock-in mice. Of note, decreasing phosphorylation of SMAD1/5/9 was detected in growth plates and primary chondrocytes from Smoc2L359R/L359R mice. Furthermore, binding affinity of mutant SMOC2 with collagen IX and HSPG in the extracellular matrix of cartilage were reduced while binding affinity with BMPRIB was intact. In addition, in contrast to previously results, that SMOC2 cannot antagonize BMP activity in the presence of a constitutively activated BMP receptor. These results support that SMOC2 with p.Leu359Arg variant act as an antagonist of canonical BMP pathway by competitively binding with BMP receptors.

genomics↗

bioRxiv2020

Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+ cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

immunology↗