Metabolic regulation has been proven to play a critical role in T cell antitumor immunity.However,cholesterol metabolism as a key component of this regulation remains largely unexplored.Herein,we found that the low-de...Metabolic regulation has been proven to play a critical role in T cell antitumor immunity.However,cholesterol metabolism as a key component of this regulation remains largely unexplored.Herein,we found that the low-density lipoprotein receptor(LDLR),which has been previously identified as a transporter for cholesterol,plays a pivotal role in regulating CD8+T cell antitumor activity.Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion,we also found a non-canonical function of LDLR in CD8+T cells:LDLR interacts with the T-cell receptor(TCR)complex and regulates TCR recycling and signaling,thus facilitating the effector function of cytotoxic T-lymphocytes(CTLs).Furthermore,we found that the tumor microenvironment(TME)downregulates CD8+T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9(PCSK9)which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs.Moreover,genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+T cells by alleviating the suppressive effect on CD8+T cells and consequently inhibit tumor progression.While previously established as a hypercholesterolemia target,this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.展开更多
Summary What is already known about this topic?Aerosol transmission of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)via sanitary pipelines in high-rise buildings is possible,however,there is a lack of ex...Summary What is already known about this topic?Aerosol transmission of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)via sanitary pipelines in high-rise buildings is possible,however,there is a lack of experimental evidence.展开更多
Figure 1.LDLR deficiency hinders the antitumor activity of CD8^(+)T cells.(A)Transcriptional level of genes involved in cholesterol transport in naïve CD8^(+)T cells,CTLs and CD8^(+)TILs(isolated at Day3 or Day7 ...Figure 1.LDLR deficiency hinders the antitumor activity of CD8^(+)T cells.(A)Transcriptional level of genes involved in cholesterol transport in naïve CD8^(+)T cells,CTLs and CD8^(+)TILs(isolated at Day3 or Day7 post CTLs adoptive transfer),(n=4).(B)LDLR expression level on CTLs and CD8^(+)TILs(isolated at Day3 post CTLs adoptive transfer),(n=4).展开更多
Structural modifications throughπ-interactions usually result in redshifts in luminescence and,as a consequence,the loss of the natural color of the chromophore.Besides,employing Si-Siσ-bridging to manipulate the el...Structural modifications throughπ-interactions usually result in redshifts in luminescence and,as a consequence,the loss of the natural color of the chromophore.Besides,employing Si-Siσ-bridging to manipulate the electronic properties of organic materials has remained largely unexplored.Herein,we report a series of novel bis-tetraphenylethenes(BTPEs)with oligosilanyl linkages,termed BTPE-Sin molecules,used to manipulate the photophysical properties of luminogens subtly throughσ–πconjugation.These oligosilanyl-bridged molecules were thermally,highly stable,and exhibited enhanced aggregation-induced emissions,as well as luminescence efficiencies while retaining most of their original color.Our current BTPEs fabrications have easy-to-operate,fast,and high-resolution identification properties toward LFPs.Also,they are highly specific to individuals,and hence,vital in forensic investigations.We achieved these features through the introduction of oligosilanyl chains that increased the lipophilicity of the significantly.This work offers a universal and straightforward approach for the generation of highly emissive organic materials and enables fine-tuning of their electronic properties for multifunctional applications.展开更多
文摘Metabolic regulation has been proven to play a critical role in T cell antitumor immunity.However,cholesterol metabolism as a key component of this regulation remains largely unexplored.Herein,we found that the low-density lipoprotein receptor(LDLR),which has been previously identified as a transporter for cholesterol,plays a pivotal role in regulating CD8+T cell antitumor activity.Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion,we also found a non-canonical function of LDLR in CD8+T cells:LDLR interacts with the T-cell receptor(TCR)complex and regulates TCR recycling and signaling,thus facilitating the effector function of cytotoxic T-lymphocytes(CTLs).Furthermore,we found that the tumor microenvironment(TME)downregulates CD8+T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9(PCSK9)which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs.Moreover,genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+T cells by alleviating the suppressive effect on CD8+T cells and consequently inhibit tumor progression.While previously established as a hypercholesterolemia target,this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.
基金Supported by the Key Program of National Natural Science Foundation of China(92043201).
文摘Summary What is already known about this topic?Aerosol transmission of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)via sanitary pipelines in high-rise buildings is possible,however,there is a lack of experimental evidence.
文摘Figure 1.LDLR deficiency hinders the antitumor activity of CD8^(+)T cells.(A)Transcriptional level of genes involved in cholesterol transport in naïve CD8^(+)T cells,CTLs and CD8^(+)TILs(isolated at Day3 or Day7 post CTLs adoptive transfer),(n=4).(B)LDLR expression level on CTLs and CD8^(+)TILs(isolated at Day3 post CTLs adoptive transfer),(n=4).
基金support was provided by the National Natural Science Foundation of China(nos.21871072 and 21801057)Organosilicon Chemistry innovation team and research funding project of Hangzhou Normal University(2019QDL019)。
文摘Structural modifications throughπ-interactions usually result in redshifts in luminescence and,as a consequence,the loss of the natural color of the chromophore.Besides,employing Si-Siσ-bridging to manipulate the electronic properties of organic materials has remained largely unexplored.Herein,we report a series of novel bis-tetraphenylethenes(BTPEs)with oligosilanyl linkages,termed BTPE-Sin molecules,used to manipulate the photophysical properties of luminogens subtly throughσ–πconjugation.These oligosilanyl-bridged molecules were thermally,highly stable,and exhibited enhanced aggregation-induced emissions,as well as luminescence efficiencies while retaining most of their original color.Our current BTPEs fabrications have easy-to-operate,fast,and high-resolution identification properties toward LFPs.Also,they are highly specific to individuals,and hence,vital in forensic investigations.We achieved these features through the introduction of oligosilanyl chains that increased the lipophilicity of the significantly.This work offers a universal and straightforward approach for the generation of highly emissive organic materials and enables fine-tuning of their electronic properties for multifunctional applications.
