查看更多>>摘要：The enrichment of regulatory T cells(Tregs)in the tumour microenvironment(TME)has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors.C-C motif chemokine receptor 8(CCR8),a marker of activated suppressive Tregs,has a significant impact on the functions of Tregs in the TME.However,the regulatory mechanism of CCR8 in Tregs remains unclear.Here,we revealed that a high level of TNF-α in the colorectal cancer(CRC)microenvironment upregulated CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor.Furthermore,in both anti-programmed cell death protein 1(anti-PD1)-responsive and anti-PD1-unresponsive tumour models,PD1 blockade induced CCR8+ Treg infiltration.In both models,Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy.Finally,we identified that TNFR2+ CCR8+ Tregs but not total Tregs were positively correlated with adverse prognosis in patients with CRC and gastric cancer.Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.
查看更多>>摘要：The transforming growth factor-beta(TGF β)signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment,making anti-TGF β agents a significant area of interest in cancer immunotherapy.However,the clin-ical translation of current anti-TGF β agents that target upstream cytokines and receptors remains challenging.Therefore,the development of small-molecule inhibitors specifically targeting SMAD4,the downstream master regulator of the TGF β pathway,would offer an alternative approach with significant therapeutic potential for anti-TGF β signaling.In this study,we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer(TR-FRET)assay in an ultrahigh-throughput screening(uHTS)1536-well plate format.This assay enables simultaneous monitoring of the protein-protein interaction between SMAD4 and SMAD3,as well as the protein-DNA interaction between SMADs and their consensus DNA-binding motif.The multiplexed TR-FRET assay exhibits high sensitivity,allowing the dynamic analysis of the SMAD4-SMAD3-DNA complex at single-amino acid resolution.Moreover,the multiplexed uHTS assay demonstrates robustness for screening small-molecule inhibitors.Through a pilot screening of an FDA-approved bioactive compound library,we identified gambogic acid and gambogenic acid as potential hit compounds.These proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4-SMAD3-DNA complex as novel anti-TGF β signaling agents.
查看更多>>摘要：Obesity is closely related to non-alcoholic fatty liver disease(NAFLD).Although sex differences in body fat distribution have been well demonstrated,little is known about the sex-specific associations between adipose tissue and the development of NAFLD.Using community-based cohort data,we evaluated the associations between magnetic resonance imaging quantified areas of abdominal adipose tissue,including visceral adipose tissue(VAT)and subcutaneous adipose tissue(SAT),and incident NAFLD in 2830 participants(1205 males and 1625 females)aged 55-70 years.During a 4.6-year median follow-up,the cumulative incidence rates of NAFLD increased with areas of VAT and SAT both in males and in females.Further analyses showed that the above-mentioned positive associations were stronger in males than in females,especially in participants under 60 years old.In contrast,these sex differences disappeared in those over 60 years old.Furthermore,the risk of developing NAFLD increased non-linearly with increasing fat area in a sex-specific pattern.Additionally,sex-specific potential mediators,such as insulin resistance,lipid metabolism,inflammation,and adipokines,may exist in the associations between adipose tissue and NAFLD.This study showed that the associations between abdominal fat and the risk of NAFLD were stratified by sex and age,highlighting the potential need for sex-and age-specific management of NAFLD.
查看更多>>摘要：As a significant member of the immune checkpoint,programmed cell death 1 ligand 1(PD-L1)plays a critical role in cancer immune escape and has become an important target for cancer immunotherapy.Clinically approved drugs mainly target the extracellular domain of PD-L1.Recently,the small cytoplasmic domain of PD-L1 has been reported to regulate PD-L1 stability and function through multiple pathways.Therefore,the intracellular domain of PD-L1 and its regulatory pathways could be promising targets for cancer therapy,expanding available strategies for combined immunotherapy.Here,we summarize the emerging roles of the PD-L1 cytoplasmic domain and its regulatory pathways.The conserved motifs,homodimerization,and posttranslational modifica-tions of the PD-L1 cytoplasmic domain have been reported to regulate the membrane anchoring,degradation,nuclear translocation,and glycosylation of PD-L1.This summary provides a comprehensive understanding of the functions of the PD-L1 cytoplasmic domain and evaluates the broad prospects for targeted therapy.
查看更多>>摘要：Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods.However,these methods have their own deficiencies that restrict the therapeutic applica-tions of such induced hepatocytes.In this study,we present a transgene-free,highly efficient chemical-induced direct reprogram-ming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts(MEFs).Using a small molecule cocktail(SMC)as an inducer,MEFs can be directly reprogrammed into hepatocyte-like cells,bypassing the intermediate stages of pluripotent and immature hepatoblasts.These chemical-induced hepatocyte-like cells(ciHeps)closely resemble mature primary hepatocytes in terms of morphology,biological behavior,gene expression patterns,marker expression levels,and hepatic functions.Furthermore,transplanted ciHeps can integrate into the liver,promote liver regeneration,and improve survival rates in mice with acute liver damage.ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function.Notably,ciHeps exhibit no tumorigenic potential either in vitro or in vivo.Mechanistically,SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps.These results indicate that this transgene-free,chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes.Additionally,this method also sheds light on the direct reprogramming of other cell types under chemical induction.
查看更多>>摘要：Lenacapavir,targeting the human immunodeficiency virus type-1(HIV-1)capsid,is the first-in-class antiretroviral drug recently approved for clinical use.The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years.Considered little more than a component of the virus shell to be shed early during infection,capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host cell factors,entering the nucleus,and directing integration.Here,we describe the key advances that led to this'capsid revolution'.
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