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Design of a novel chimeric peptide via dual blockade of CD47/SIRPαand PD-1/PD-L1 for cancer immunotherapy

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中国科学:生命科学英文版 2023年第10期66卷 2310-2328页

作者： Zheng Hu Wanqiong Li Shaomeng Chen Danhong Chen Ran Xu Danlu Zheng Xin Yang Shuzhen Li Xiuman Zhou Xiaoshuang Niu Youmei Xiao Zhuoying He Huihao Li Juan Liu xinghua sui Yanfeng Gao School of Pharmaceutical Sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China School of Medicine Shenzhen Campus of Sun Yat-sen UniversitySun Yat-sen UniversityShenzhen 518107China

Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types,only a small subset of patients can benefit from PD-1/PD-L1 blockade.CD47 expressed on tumor cells protects them from phagocytosis through interaction with SIRPαon macrophages,while PD-L1 dampens T cell-mediated tumor killing.Therefore,dual targeting PD-L1 and CD47 may improve the efficacy of cancer immunotherapy.A chimeric peptide Pal-DMPOP was designed by conjugating the double mutation of CD47/SIRPαblocking peptide(DMP)with the truncation of PD-1/PD-L1 blocking peptide OPBP-1(8-12)and was modified by a palmitic acid tail.Pal-DMPOP can significantly enhance macrophage-mediated phagocytosis of tumor cells and activate primary T cells to secret IFN-γin vitro.Due to its superior hydrolysis-resistant activity as well as tumor tissue and lymph node targeting properties,Pal-DMPOP elicited stronger anti-tumor potency than Pal-DMP or OPBP-1(8-12)in immune-competent MC38 tumor-bearing mice.The in vivo anti-tumor activity was further validated in the colorectal CT26 tumor model.Furthermore,Pal-DMPOP mobilized macrophage and T-cell anti-tumor responses with minimal toxicity.Overall,the first bispecific CD47/SIRPαand PD-1/PD-L1 dual-blockade chimeric peptide was designed and exhibited synergistic anti-tumor efficacy via CD8^(+)T cell activation and macrophage-mediated immune response.The strategy could pave the way for designing effective therapeutic agents for cancer immunotherapy.

关键词： CD47 PD-L1 cancer immunotherapy immune checkpoint blockade peptide

A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigenspecific CD8^+ T cell responses

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Acta Pharmaceutica Sinica B 2020年第6期10卷 1047-1060页

作者： Wenjie Zhai Xiuman Zhou Hongfei Wang Wanqiong Li Guanyu Chen xinghua sui Guodong Li Yuanming Qi Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityGuangzhou 510006China

PD-1 and CTLA-4 antibodies offer great hope for cancer immunotherapy.However,many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune activation.The combination of checkpoint blockers has been proposed to increase the response rates.Besides,antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration problems.In this study,we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting LAG-3.As a result,C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR(MHC-II).Additionally,C25 could significantly stimulate CD8^+T cell activation in human PBMCs.The results also demonstrated that C25 could inhibit tumor growth of CT26,B16 and B 16-OVA bearing mice,and the infiltration of CD8^+T cells was significantly increased while FOXP3^+Tregs significantly decreased in the tumor site.Furthermore,the secretion of IFN-γby CD8^+T cells in spleen,draining lymph nodes and especially in the tumors was promoted.Simultaneously,we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide,and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects via CD8+T cells but not direct killing.In conclusion,cyclic peptide C25 provides a rationale for targeting the immune checkpoint,by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity,and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.

关键词： LAG-3 Phage display Cyclic peptide Immune checkpoint blockade CD8^+T cell Cancer immunotherapy

Tryptophan 2,3-dioxygenase 2 controls M2 macrophages polarization to promote esophageal squamous cell carcinoma progression via AKT/GSK3β/IL-8 signaling pathway

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2835-2849页

作者： Yumiao Zhao Jiaxin Sun Yin Li Xiuman Zhou Wenjie Zhai Yahong Wu Guanyu Chen Shanshan Gou xinghua sui Wenshan Zhao Lu Qiu Yongjie Yao Yixuan Sun Chunxia Chen Yuanming Qi Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China Thoracic Surgery Department National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518107China

Tryptophan 2,3-dioxygnease 2(TDO2) is specific for metabolizing tryptophan to kynurenine(KYN),which plays a critical role in mediating immune escape of cancer.Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers,its tumor-promoting role in esophageal squamous cell carcinoma(ESCC) remains unclear.Here,we observed that TDO2 was overexpressed in ESCC tis sues and correlated significantly with lymph node metastasis,advanced clinical stage,and unfavorable prognosis.Functional experiments showed that TDO2 promoted tumor cell proliferation,migration,and colony formation,which could be prevented by inhibition of TDO2 and aryl hydrocarb on receptor(AHR).Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model,tumor burden of C57 BL/6 mice with ESCC induced by 4-NQO,enhance the expression of phosphorylated AKT,with subsequent pho sphorylation of GSK3β,and polarization of M2 macrophages by upregulating interleukin-8(IL-8) to accelerate tumor progression in the tumor microenvironment(TME).Collectively,our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC,and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.

关键词： Tryptophan 2,3-dioxygenase 2 M2 macrophage Esophageal squamous cell carcinoma IL-8 KYN

G-quadruplexes folding mediates downregulation of PBX1 expression in melanoma

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Signal Transduction and Targeted Therapy 2023年第2期8卷 344-347页

作者： Yutong sui Feilin Liu Song Zheng Xiaomei Liu Pingli Sun Chunli Yao Yingyao Zhang Hongwen Gao xinghua Gao Jinyu Liu Department of Toxicology School of Public HealthJilin UniversityChangchunChina The Second Hospital of Jilin University ChangchunChina Department of Dermatology The First Hospital of China Medical UniversityKey Laboratory of ImmunodermatologyMinistry of Education/Public HealthShenyangChina

Dear Editor,Pre-B-cell leukemia homeobox transcription factor 1(PBX1)is identified at t(1;19)chromosomal translocations in acute pre-B-cell leukemia and is involved in regulating multiple biological processes.1 Importantly,accumulating evidence have suggested that dysregulation of PBX1 have been shown to be involved in tumorigenesis,poor prognosis and drug resistance.1 It has been shown that the expression of PBX1 is increased in melanoma cells and overexpression of PBX1 significantly promotes the melanoma cell growth.

关键词： melanoma acute processes

基于微波干涉雷达的桥梁拉索基频快速识别方法研究及应用

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世界桥梁 2023年第6期51卷 91-97页

作者：李力李兴华谈遂桥梁智能与绿色建造全国重点实验室湖北武汉430034 中铁大桥科学研究院有限公司湖北武汉430034 中铁大桥局集团有限公司湖北武汉430050 高速铁路建造技术国家工程研究中心湖南长沙410075

针对微波干涉雷达现场识别桥梁拉索基频过程中存在操作繁琐、人机交互能力差等问题,基于微波干涉雷达测量拉索基频的原理,提出了一种可快速提取拉索位置参数的方法,运用指数平滑法、峰值检测法和自相关算法对雷达散射波形数据进行分析,... 详细信息

针对微波干涉雷达现场识别桥梁拉索基频过程中存在操作繁琐、人机交互能力差等问题,基于微波干涉雷达测量拉索基频的原理,提出了一种可快速提取拉索位置参数的方法,运用指数平滑法、峰值检测法和自相关算法对雷达散射波形数据进行分析,自动提取拉索位置参数进行拉索基频的快速识别。采用该方法对2座大型斜拉桥斜拉索频率进行识别,并与采用加速度传感器法的拉索频率结果进行对比,结果表明:采用微波干涉雷达识别的拉索频率与加速度传感器法的实测频率相对偏差率在±1.5%以内,验证了该方法的可靠性;基于微波干涉雷达的桥梁拉索基频快速识别方法省时省力,可一次性快速获取多根拉索的位置参数并进行基频识别,自动化程度高。

关键词：桥梁拉索基频微波干涉雷达拉索位置参数快速识别频率测试工程应用

教育政策执行偏差的主体因素及对策分析——计划行为理论视角

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广西社会科学 2018年第12期 222-226页

作者：隋幸华北京大学教育学院北京100871 湖南理工学院教务处湖南岳阳414006

教育政策执行过程中时常会出现不同程度偏差,从执行主体行为视角来看主要表现为:主体执行政策的部分内容、主体替换原政策内容执行、主体故意应付政策执行。根据计划行为理论分析发现,主要有三个因素起着重要的影响作用:执行者对执行该... 详细信息

教育政策执行过程中时常会出现不同程度偏差,从执行主体行为视角来看主要表现为:主体执行政策的部分内容、主体替换原政策内容执行、主体故意应付政策执行。根据计划行为理论分析发现,主要有三个因素起着重要的影响作用:执行者对执行该教育政策的态度、执行者感知到执行该政策的社会压力、执行者感知到自己具有什么样的能力去执行该行为。为减少教育政策执行偏差,应确保政策内容的务实和清晰,为政策执行配备充足的资源与措施,提高政策执行者整体综合素质。

关键词：教育政策执行偏差主体因素计划行为理论

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四路激光跟踪柔性坐标测量系统的跟踪器设计

仪器仪表学报 2005年第12期26卷 1253-1256,1261页

作者：隋修武张国雄李杏华刘欣丽天津大学精密测试技术及仪器国家重点实验室天津300072

激光跟踪器是激光跟踪坐标测量系统的关键部件。采用双电机驱动的单转镜结构,模拟式的P ID与单片机的数字式P ID相结合的闭环控制方案,设计了一种新型的激光跟踪器。该跟踪器具有跟踪快速、平稳,反射基点在跟踪过程中保持不动,跟踪精度... 详细信息

激光跟踪器是激光跟踪坐标测量系统的关键部件。采用双电机驱动的单转镜结构,模拟式的P ID与单片机的数字式P ID相结合的闭环控制方案,设计了一种新型的激光跟踪器。该跟踪器具有跟踪快速、平稳,反射基点在跟踪过程中保持不动,跟踪精度高等优点,并成功的应用于四路激光跟踪柔性坐标测量系统。实验表明,激光跟踪测量系统的有效跟踪速度优于0.4m/s,综合测量精度1.2μm。

关键词：激光干涉仪激光跟踪系统坐标测量机 PID 光电位置检测器单片机

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大众化背景下大学通识教育的特点

长沙大学学报 2014年第6期28卷 117-119页

作者：隋幸华湖南理工学院教务处湖南岳阳414006

在高等教育大众化系统中,教育的理念、目的、组织、结构、功能、管理等方面都有着各自的特征表现,同样,大学通识教育在此阶段也表现出一定的特征。在大众化阶段,大学通识教育具有教育目的更趋现实性、教育内容层级分明、教育形式更为丰... 详细信息

在高等教育大众化系统中,教育的理念、目的、组织、结构、功能、管理等方面都有着各自的特征表现,同样,大学通识教育在此阶段也表现出一定的特征。在大众化阶段,大学通识教育具有教育目的更趋现实性、教育内容层级分明、教育形式更为丰富、对社会发展影响愈深等特征。

关键词：大众化通识教育特点

内蒙古荒漠草原植被盖度的空间异质性动态分析

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生态学报 2012年第13期32卷 4017-4024页

作者：颜亮周广胜张峰隋兴华平晓燕中国科学院植物研究所植被与环境变化国家重点实验室北京100093 中国科学院研究生院北京100049 中国气象科学研究院北京100081

利用半方差函数分析法对内蒙古荒漠草原生长盛期(6—8月)的植被盖度时空变异特征的研究表明,荒漠草原生长盛期的植被盖度半方差函数形态符合指数模型,但函数曲线的形态和各参数在不同月份变化较大。其中,6月的植被盖度变程最大,达到100 ... 详细信息

利用半方差函数分析法对内蒙古荒漠草原生长盛期(6—8月)的植被盖度时空变异特征的研究表明,荒漠草原生长盛期的植被盖度半方差函数形态符合指数模型,但函数曲线的形态和各参数在不同月份变化较大。其中,6月的植被盖度变程最大,达到100 m;7月植被盖度的半方差函数形态具有巢式等级结构;8月植被盖度的变程最小,仅为15 m,但空间变异程度最高。3个月的结构比介于72%—85%,具有较强的空间自相关。各向异性分析表明,6月植被盖度在135°方向的半方差函数值明显低于其它3个方向(0°、45°、90°),具有各向异性特征;而7月和8月植被盖度的各向异性比接近于1,表现为各向同性。研究结果表明,荒漠草原植被盖度空间异质性的时间动态不容忽视,在野外采样或制图时,要根据时间合理控制采样范围。

关键词：荒漠草原空间异质性半方差函数时间动态植被盖度