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Frontiers of Medicine 2023年第5期17卷 805-822页

作者： Liming Liao Huilin Xu Yuhan Zhao Xiaofeng Zheng State Key Laboratory of Protein and Plant Gene Research Department of Biochemistry and Molecular BiologySchool of Life SciencesPeking UniversityBeijing100871China

Immunotherapies based on immune checkpoint blockade(ICB)have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade.To date,immune checkpoint inhibitors(ICIs)of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy.Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers,however,a large subset of refractory patients presents poor responsiveness to ICB therapy;and the underlying mechanism remains elusive.Recently,numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment(TME)with various products of metabolism,and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy.Nevertheless,a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance.Here,we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints(CTLA-4,PD-1,and PD-L1)to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

关键词： CTLA-4 PD-1 PD-L1 immune checkpoint blockade(ICB) metabolic reprogramming combined tumor therapeutic strategies

The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8^(+)T-cell immunity

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Cellular & Molecular Immunology 2023年第12期20卷 1445-1456页

作者： Jizhang Yu Jikai Cui Xi Zhang Heng Xu Zhang Chen Yuan Li Yuqing Niu Song Wang Shuan Ran Yanqiang Zou Weicong Ye Dan Zhang Cheng Zhou Jiahong Xia Jie Wu Department of Cardiovascular Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Key Laboratory of Organ Transplantation Ministry of EducationNHC Key Laboratory of Organ TransplantationKey Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhanChina Center for Translational Medicine Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Institute of Translational Medicine Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Cancer Center Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Immune checkpoint blockade(ICB),including anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4),benefits only a limited number of patients with cancer.Understanding the in-depth regulatory mechanism of CTLA-4 protein stability and its functional significance may help identify ICB resistance mechanisms and assist in the development of novel immunotherapeutic modalities to improve ICB efficacy.Here,we identified that TNF receptor-associated factor 6(TRAF6)mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of CTLA-4.Moreover,by using TRAF6-deficient mice and retroviral overexpression experiments,we demonstrated that TRAF6 promotes CTLA-4 degradation in a T-cell-intrinsic manner,which is dependent on the RING domain of TRAF6.This intrinsic regulatory mechanism contributes to CD8+T-cell-mediated antitumor immunity in vivo.Additionally,by using an OX40 agonist,we demonstrated that the OX40-TRAF6 axis is responsible for CTLA-4 degradation,thereby controlling antitumor immunity in both tumor-bearing mice and patients with cancer.Overall,our findings demonstrate that the OX40-TRAF6 axis promotes CTLA-4 degradation and is a potential therapeutic target for the improvement of T-cell-based immunotherapies.

关键词： Antitumor immunity CD8^(+)T cell T-cell-based immunotherapy TRAF6 CTLA-4

cAMP差异调控CD39、CTLA-4、PD-1T细胞亚群产生

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中国免疫学杂志 2024年

作者：蔡雨俊郝振平郑永唐田仁荣大理大学药学院中国科学技术大学生命科学学院中国科学院昆明动物研究所中国科学院动物模型与人类疾病机理重点实验室

目的分析CD39、CTLA-4及PD-1在T细胞上的表达及表达模型，探讨环磷酸腺苷(cAMP)对其表达影响，解析调控其表达的关键通路。方法通过腺苷酸环化酶(ACs)激活剂、磷酸二酯酶(PDE)抑制剂、蛋白激酶A(PKA)抑制剂以及PKA-CREB抑制剂等小分... 详细信息

目的分析CD39、CTLA-4及PD-1在T细胞上的表达及表达模型，探讨环磷酸腺苷(cAMP)对其表达影响，解析调控其表达的关键通路。方法通过腺苷酸环化酶(ACs)激活剂、磷酸二酯酶(PDE)抑制剂、蛋白激酶A(PKA)抑制剂以及PKA-CREB抑制剂等小分子化合物体外刺激猕猴外周血单个核细胞，流式细胞术检测CD39、CTLA-4、PD-1阳性(CD39+、CTLA-4+、PD-1+)T细胞的比率变化，分析其表达模式，对比小分子对表达/共表达的阳性细胞比率影响，明确表达模式及调控表达的分子与通路。结果正常猕猴的CD4+T和CD8+T细胞中CD39+、CTLA-4+和PD-1+细胞比率较低，且阳性细胞仅表达其中的一种分子为主；增加胞内cAMP浓度，不影响CD39+T细胞比率，显著增加CTLA-4+T细胞比率，降低PD-1+CD8+T细胞比率，涉及细胞群为CTLA-4和PD-1单表达的细胞群；抑制PKA活性可降低PDE广谱抑制剂3-异丁基-1-甲基黄嘌呤(IBMX)对CTLA-4表达的增效作用，但不影响PD-1的表达；交换蛋白激动剂不影响CTLA-4的表达，但下调PD-1+CD4+/CD8+T细胞比率；PDE4B选择性抑制剂对CTLA-4的上调作用与IBMX相似，而PDE3和PDE5A选择性抑制剂对PD-1表达的调控与IBMX相似。结论 CD39、CTLA-4和PD-1在T细胞上有不同表达模型，但受cAMP水平的不同调控，而且参与表达调控的cAMP下游信号通路不同。

关键词： CD39 CTLA-4 PD-1 cAMP T细胞

Cardiovascular toxicity with CTLA-4 inhibitors in cancer patients:A meta-analysis

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Cancer Innovation 2024年第3期3卷 49-64页

作者： Huiyi Liu Lu Fu Shuyu Jin Xingdong Ye Yanlin Chen Sijia Pu Yumei Xue Department of Cardiology Guangdong Cardiovascular InstituteGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina The Second School of Clinical Medicine Southern Medical UniversityGuangzhouGuangdongChina School of Medicine South China University of TechnologyGuangzhouGuangdongChina Guangdong Provincial Key Laboratory of Clinical Pharmacology Research Center of Medical SciencesGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina

Background:With the emergence of cytotoxic T lymphocyte-associated protein-4(CTLA-4)inhibitors,the outcomes of patients with malignant tumors have improved significantly.However,the incidence of cardiovascular adverse events has also increased,which can affect tumor treatment.In this study,we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy.Methods:Randomized clinical trials published in English from January 1,2013,to November 30,2022,were searched using the Cochrane Library and PubMed databases.All included trials examined all grade and grades 3–5 cardiac and vascular adverse events.These involved comparisons of CTLA-4 inhibitors to placebo,CTLA-4 inhibitors plus chemotherapy to chemotherapy alone,CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone,and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent.The odds ratio(OR)and corresponding 95%confidence intervals(CIs)were calculated using the Mantel-Haenszel method.Results:Overall,20 trials were included.CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity(OR=1.33,95%CI:1.00–1.75,p=0.05).The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors(OR=1.73,95%CI:1.13–2.65,p=0.01),as well as the incidence rate of grades 3–5 cardiovascular adverse events(OR=2.00,95%CI:1.08–3.70,p=0.03).Compared with the non-CTLA-4 inhibitor group,CTLA-4 inhibitors plus chemotherapy,PD-1/PD-L1 inhibitors,or target agent did not significantly affect the incidence of cardiac and vascular toxicity.The incidence of grades 3–5 cardiac failure,hypertension,pericardial effusion,myocarditis,and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor,but the data were not statistically significant.Conclusion:Our findings suggest that the incidence rate of all cardiovascular toxicity an

关键词： cardiovascular toxicity CTLA-4 inhibitors malignancies

CTLA-4+49 A/G Polymorphism and the Risk of Lung Cancer:a Meta-analysis

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中国肺癌杂志 2021年第3期24卷 173-181页

作者： Zhengliang WEI Shaoqin ZHANG Jian HU Department of Cardiothoracic Surgery Shengzhou People's Hospital(the First Affiliated Hospital of Zhejiang University Shengzhou Branch)Shengzhou 312400China Department of Cardiothoracic Surgery The First Affiliated HospitalZhejiang UniversityHangzhou 310006China

Background and objective:Lung cancer is one of the malignant tumors.Gene mutations associated with cellular immune function and regulating the activation and proliferation of immune cells.Several publications have explored the relationship between cytotoxic T lymphocyte antigen-4(CTLA-4)+49 adenine(A)/guanine(G)polymorphism and susceptibility of lung cancer,but the results remain controversial.Thus,we performed this meta-analysis to derive a more comprehensive estimation of the relationship.Methods:All articles addressed lung cancer and polymorphisms of CTLA-4 were searched from the Pub Med,EMBASE databases published up to June 29,2019.Odds ratios(ORs)with 95%confidence intervals(CIs)were used to assess the strength of association.Publication bias of relevant studies was examined via Begg’s test and funnel plots.Results:The meta-analysis included 8 case-control studies covering 4,430 lung cancer patients and 5,198 healthy controls from September 2008 to April 2020.The overall eligible data indicated that CTLA-4+49 A/G polymorphisms did not correlate with the elevated lung cancer risk in all genetic comparison models(dominant model:OR=1.037,95%CI:0.925-1.161;recessive model:OR=0.968,95%CI:0.888-1.055;allele model:OR=0.992,95%CI:0.933-1.054;homozygous model:OR=0.980,95%CI:0.857-1.121;heterozygous model:OR=1.023,95%CI:0.906-1.154).In further stratified analyses,CTLA-4+49 A/G polymorphism was found to be significantly associated with susceptibility to NSCLC in these models(dominant model:OR=1.404,95%CI:1.074-1.836;allele model:OR=1.273,95%CI:1.034-1.565;homozygous model:OR=1.553,95%CI:1.044-2.310;heterozygous model:OR=1.308,95%CI:1.062-1.611).Conclusion:CTLA-4+49 A/G polymorphism were not associated with the risk of lung cancer but might be a risk factor only in NSCLC.

关键词： CTLA-4 Polymorphism Lung neoplasms Meta-analysis

Degradation of CTLA-4 balances toxicity and efficacy

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Science Bulletin 2019年第19期64卷 1388-1389页

作者： Zhenhua Ren Yang-Xin Fu The Department of Pathology UT Southwestern Medical CenterDallasTX75235-9072USA The Department of Immunology UT Southwestern Medical CenterDallasTX75235-9072USA

The notorious side effects of anti-CTLA-4 limit its use in the clinic,but what causes the severe side effects remains largely unclear.Zhang et al.[1]elucidated antibody-induced CTLA-4lysosomal degradation as a new mechanism accounting for the severe immunotherapy-related adverse effects and limited efficacy of anti-CTLA-4 therapy.CTLA-4 expresses on regulatory T cells(Tregs)and activated CD8 and CD4 effector cells.

关键词： Degradation CTLA-4 toxicity

PD-1/PD-L1与CTLA-4联合治疗实体瘤患者有效性和安全性的Meta分析

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中国医院药学杂志 2022年第17期42卷 1808-1816页

作者：曾洁陈瑞祥李辉温瑾大理大学药学院云南大理671000 云南省第三人民医院药剂科云南昆明650011

目的:系统评价PD-1/PD-L1与CTLA-4联合治疗对比PD-1/PD-L1单药治疗实体瘤患者的有效性和安全性,旨在为临床用药提供循证参考。方法:计算机检索PubMed、Embase、Cochrane Library、中国知网、CBM、维普和万方数据,检索时限均为各数据库... 详细信息

目的:系统评价PD-1/PD-L1与CTLA-4联合治疗对比PD-1/PD-L1单药治疗实体瘤患者的有效性和安全性,旨在为临床用药提供循证参考。方法:计算机检索PubMed、Embase、Cochrane Library、中国知网、CBM、维普和万方数据,检索时限均为各数据库建库至2021年11月。根据纳入与排除标准筛选文献后,采用Cochrane系统评价员手册5.1.0推荐的偏倚风险评估工具对纳入文献质量进行评价;采用Rev Man 5.4软件进行Meta分析;采用倒漏斗图进行发表偏倚分析。结果:共纳入22项研究,共计8535例患者。Meta分析结果显示,从生存指标方面分析,PD-1/PD-L1与CTLA-4联合治疗显著改善实体瘤患者的客观反应率(ORR)、疾病控制率(DCR)和无进展生存期(PFS),但总生存期(OS)改善无统计学差异。亚组分析结果显示,PD-1/PD-L1与CTLA-4联合治疗能显著改善黑色素瘤患者的ORR和PFS,而OS改善无统计学差异;能显著改善肺癌患者的PFS,而ORR和OS改善无统计学差异;显著改善其他实体瘤患者的ORR和DCR,而PFS和OS改善无统计学差异。从安全指标方面分析,PD-1/PD-L1与CTLA-4联合治疗显著增加实体瘤患者的所有级别和3~4级不良反应发生率、死亡率以及中止治疗率。亚组分析结果显示,PD-1/PD-L1与CTLA-4联合治疗能显著增加黑色素瘤和其他实体瘤患者的3~4级不良反应发生率和中止治疗率,显著增加肺癌患者所有级别和3~4级不良反应发生率、死亡率以及中止治疗率。结论:PD-1/PD-L1和CTLA-4联合治疗与PD-1/PD-L1单药治疗相比,能显著改善实体瘤患者的PFS、DCR和ORR,但是也显著增加实体瘤患者治疗相关不良反应发生率。

关键词： PD-1/PD-L1 CTLA-4 联合治疗有效性安全性 Meta分析

以CRSIPR/Cas9技术删除CTLA-4后CTL抗裸鼠结肠癌移植瘤的效果

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中国肿瘤生物治疗杂志 2020年第3期27卷 221-227页

作者：师龙耿耸松蔡子琪韩锦胜赵咫龙张伟宋鸿涛孟桐羽蔡建辉河北医科大学第二医院血管外科河北石家庄050000 浓孚雨(河北)生物医药股份有限公司河北石家庄050000 沧州中西医结合医院胃肠腹壁疝外科河北沧州061000 锦州医科大学附属第三医院肝胆外科辽宁锦州121000 邯郸市中心医院普外二科河北邯郸056001 石家庄市第二医院周围血管外科河北石家庄050000 石家庄市人民医院妇科河北石家庄050000 河北省人民医院普外科&肿瘤科河北石家庄050000

目的:探讨使用CRSIPR/Cas9技术删除CTL的免疫检查点CTLA-4后CTL的抗裸鼠结肠癌移植瘤的效果及其作用机制。方法:针对CTLA-4设计特异性小向导RNA(small guide RNA,sgRNA)并构建sgRNA/Cas9质粒,使用慢病毒载体转染质粒至CTL获得删除CTLA-4... 详细信息

目的:探讨使用CRSIPR/Cas9技术删除CTL的免疫检查点CTLA-4后CTL的抗裸鼠结肠癌移植瘤的效果及其作用机制。方法:针对CTLA-4设计特异性小向导RNA(small guide RNA,sgRNA)并构建sgRNA/Cas9质粒,使用慢病毒载体转染质粒至CTL获得删除CTLA-4的CTL(CTLA-4 KO CTL),并验证质粒的转染效率和CTLA-4的删除效率。BALB/c裸鼠随机分为2组进行实验,预防性注射CTLA-4 KO CTL(实验组)及CTL(对照组),3 d后接种结肠癌细胞株LS174-T,观察成瘤率及成瘤时间。建立结肠癌移植瘤裸鼠模型,成瘤后裸鼠随机分为2组,分别给予CTLA-4 KO CTL(实验组)及CTL(对照组)进行细胞治疗,观察移植瘤的体积、裸鼠的生存时间,并检测移植瘤裸鼠血清中TNF-α及IFN-γ分泌水平。结果:设计sgRNA并成功构建以慢病毒为载体的CRSIPR/Cas9系统,使用构建好的CRSIPR/Cas9系统转染CTL细胞,转染效率最高可达(28.80±0.62)%,转染后以流式细胞术检测CTLA-4的删除效率,CTLA-4 KO CTL组的CTLA-4表达较CTL组显著降低[(0.91±0.25)%vs(42.70±2.72)%,P4)mm^3,P42 d,P4)vs(148.26±20.07)pg/ml,PCTLA-4后可以显著抑制裸鼠结肠癌移植瘤的成瘤率、增强CTL对荷结肠癌裸鼠的抗肿瘤作用,并明显增高荷瘤鼠血清中TNF-α和IFN-γ水平。

关键词： CRSIPR/Cas9 CTLA-4 CTL 结肠癌移植瘤免疫治疗

TIPE2、FOXP3和CTLA-4在慢性肝炎、肝硬化和肝细胞癌患者外周血单个核细胞中的表达及意义

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TIPE2、FOXP3和CTLA-4在慢性肝炎、肝硬化和肝细胞癌患者外周血单...

作者：纪雷河北医科大学

学位级别：硕士

目的:分析慢性肝炎、肝硬化及肝细胞癌患者外周血单个核细胞中TIPE2、FOXP3及CTLA-4 mRNA的表达情况,探讨TIPE2、FOXP3及CTLA-4在不同肝脏疾病发生和发展中的意义。方法:1.病例选择收集来自2020年10月至2021年11月河北医科大学第三医院... 详细信息

目的:分析慢性肝炎、肝硬化及肝细胞癌患者外周血单个核细胞中TIPE2、FOXP3及CTLA-4 mRNA的表达情况,探讨TIPE2、FOXP3及CTLA-4在不同肝脏疾病发生和发展中的意义。方法:1.病例选择收集来自2020年10月至2021年11月河北医科大学第三医院中西医结合肝病科门诊及住院患者80例,其中慢性乙型肝炎(慢性肝炎)患者28例,乙肝肝硬化(肝硬化)患者28例,乙肝病毒相关肝细胞癌(肝细胞癌)患者24例,诊断标准依据2019年《慢性乙型肝炎防治指南》、《肝硬化诊治指南》以及2017年《原发性肝癌诊疗指南》,所有入组患者1年内均未应用免疫调节药物治疗。同时排除合并其他病毒性肝炎重叠感染以及其他肝脏疾病或其他系统严重疾病者。同期选择我院体检中心20例健康志愿者作健康对照。所有患者及志愿者抽取空腹抗凝静脉血7至10ml,用于分离外周血单个核细胞检测。2.研究方法收集入组患者及健康志愿者的临床资料及实验室指标,分析比较不同肝脏疾病患者间的差异。同时收集入组患者及健康志愿者的外周血7至10ml,Ficoll密度梯度离心法分离PBMCs,应用Trizol一步法提取PBMCs中的总RNA,反转录呈c DNA,应用实时荧光定量PCR法检测TIPE2、FOXP3和CTLA-4 mRNA的表达情况,并比较各组间的差异。应用SPSS 21.0统计学软件,组间比较采用t检验或单因素方差分析比较组间差异,Pearson分析TIPE2、FOXP3及CTLA-4与临床指标的相关性。结果:1.不同肝脏疾病与健康对照组中TIPE2、FOXP3及CTLA-4mRNA的表达:慢性肝炎、肝硬化及肝细胞癌患者TIPE2 mRNA的表达水平低于健康对照组,肝细胞癌患者TIPE2 mRNA的表达低于慢性肝炎、肝硬化患者。慢性肝炎、肝硬化及肝细胞癌患者FOXP3、CTLA-4mRNA的表达水平高于健康对照组,肝细胞癌患者FOXP3、CTLA-4mRNA的表达高于慢性肝炎、肝硬化患者。2.TIPE2、FOXP3及CTLA-4 mRNA的表达水平与肝细胞损伤程度的关系:ALT、AST异常组TIPE2 mRNA的表达低于ALT、AST正常组,TBil异常组TIPE2 mRNA的表达与TBil正常组无统计学差异。FOXP3、CTLA-4 mRNA的表达水平在ALT、AST及TBil异常组明显高于ALT、AST及TBil正常组。3.TIPE2、FOXP3及CTLA-4 mRNA的表达水平与临床指标相关性分析:TIPE2 mRNA的表达与WBC、N、NLR及PLR呈负相关,与L、PLT呈正相关。而FOXP3、CTLA-4 mRNA的表达与WBC、N、NLR及PLR呈正相关,与L、PLT呈负相关。TIPE2 mRNA的表达与ALT、AST呈负相关,而FOXP3及CTLA-4 mRNA的表达与ALT、AST呈正相关。4.TIPE2 mRNA的表达与FOXP3、CTLA-4 mRNA的表达呈负相关。结论:1.TIPE2、FOXP3及CTLA-4参与了慢性肝炎发展至肝硬化、肝细胞癌的进展过程。2.TIPE2 mRNA的表达与ALT、AST及NLR、PLR呈负相关,提示TIPE2可减轻肝细胞损伤,负性调控慢性肝炎、肝硬化、肝细胞癌患者的炎症反应,在一定程度上减轻肝细胞受损程度。3.FOXP3及CTLA-4 mRNA的表达与ALT、AST及NLR、PLR呈正相关,提示FOXP3及CTLA-4可通过调节Treg细胞功能促进慢性炎症反应并加重肝细胞受损。4.TIPE2 mRNA的表达与Treg细胞表面标志性分子FOXP3及CTLA-4 mRNA的表达呈负相关,提示TIPE2作为免疫负调控分子可能通过调控FOXP3及CTLA-4的表达,从而影响Treg细胞的免疫功能,在肝脏疾病的发生和发展中发挥一定的作用。

关键词： TIPE2 FOXP3 CTLA-4 外周血单个核细胞肝脏疾病

脂质体辅助递送CTLA-4 siRNA通过激活系统性抗肿瘤免疫反应抑制肾细胞癌生长

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现代肿瘤医学 2022年第14期30卷 2515-2520页

作者：拜合提亚·阿扎提李前进刘强王玉杰新疆医科大学第一附属医院泌尿外科新疆乌鲁木齐830054

目的:探索携带CTLA-4 siRNA的适配子偶联脂质体颗粒是否可以激活肿瘤部位的抗肿瘤免疫反应,抑制肾细胞癌的生长。方法:采用薄膜水化法制备脂质体;使用透射电子显微镜观察脂质体的形态和结构;用Zetasizer测量Zeta电位;共孵育实验观察靶... 详细信息

目的:探索携带CTLA-4 siRNA的适配子偶联脂质体颗粒是否可以激活肿瘤部位的抗肿瘤免疫反应,抑制肾细胞癌的生长。方法:采用薄膜水化法制备脂质体;使用透射电子显微镜观察脂质体的形态和结构;用Zetasizer测量Zeta电位;共孵育实验观察靶细胞对Lipo-siRNA的摄取;qPCR检测Lipo-siRNA对CTLA-4基因的沉默;小鼠移植瘤模型检测Lipo-siRNA的体内抑瘤能力;流式细胞术检测肿瘤浸润T细胞的激活状态;免疫荧光法检测肿瘤浸润T细胞的数目。结果:成功制备Lipo-siRNA,电镜结果显示其具有双层球状结构;Zetasizer测得其Zeta电位为(+20.53±2.66)mV;荧光显微镜观察结果表明Lipo-siRNA可以被靶细胞有效摄取,qPCR检测Lipo-siRNA可以显著降低CTLA-4基因的表达(PCTLA-4的表达(PCTLA-4 siRNA靶向肿瘤细胞,激活肿瘤部位的抗肿瘤免疫反应,抑制肿瘤的生长,对肾细胞癌的治疗具有潜在的临床应用价值。

关键词：肾细胞癌脂质体 AS1411 siRNA CTLA-4