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| 1 | 肿瘤细胞中PD-L1表达调控机制的研究进展显示文摘程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨膜蛋白,在正常组织中广泛表达。在正常生理条件下,PD-1和PD-L1之间的胞外结合通过抑制CTLs活性从而阻止自身免疫疾病的发生。然而,PD-L1在黑色素瘤、肺癌、肾细胞癌等恶性肿瘤中的异常上调表达通过促进PD-1/PD-L1介导的CTLs失活导致癌细胞逃避免疫监控。近年来,相关研究分别从基因扩增、染色质修饰、转录与转录后修饰、翻译与翻译后修饰等角度阐述了PD-L1表达调控的分子机制。同时,针对PD-1/PD-L1轴的免疫检查点阻断治疗在多种恶性肿瘤的临床治疗中展现出了较好的疗效。该文系统总结了近年来癌细胞中的PD-L1表达调控机制研究领域的重要成果,并在此基础上展望了针对PD-1/PD-L1轴的肿瘤免疫治疗的应用前景。 | 姜茹斌 张凯瑞 葛源 | 2021 | 中国细胞生物学学报2021，43，12： | 5 |
| 2 | Tumor immune checkpoints and their associated inhibitors显示文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy. | Zerui GAO Xingyi LING Chengyu SHI Ying WANG Aifu LIN | 2022 | Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)2022，23，10： | 4 |
| 3 | 非小细胞肺癌中卵巢肿瘤泛素异肽酶1与程序性死亡受体-1配体的表达相关性显示文摘目的探讨非小细胞肺癌(NSCLC)中卵巢肿瘤泛素异肽酶1(OTUB1)与程序性死亡受体-1配体(PD-L1)的相关性。方法分析肿瘤基因组数据库(TCGA)中NSCLC与癌旁正常组织OTUB1 mRNA的差异性。基于基因表达谱数据动态分析(GEPIA)探讨NSCLC中OTUB1与PD-L1 mRNA表达相关性。免疫组化法检测46例NSCLC及41例癌旁正常组织蜡块OTUB1及PD-L1蛋白表达,收集临床病例数据及随访资料。分析OTUB1在癌组织与癌旁组织中的表达差异,OTUB1与PD-L1相关性、临床病理特征的关系以及无复发生存期(RFS)预测意义。结果 NSCLC与癌旁正常组织的OTUB1 mRNA及蛋白表达差异均有统计学意义(P<0.05)。NSCLC的OTUB1与PD-L1 mRNA无相关性(P>0.05),但两者蛋白表达有相关性(P=0.029)。OTUB1与TNM分期有相关性(P=0.039),与年龄、吸烟史、分化程度、转移淋巴结数及病理类型无相关性(P>0.05)。Kaplan-Meier分析显示,TNM分期(P<0.001)、转移淋巴结数(P=0.001)及分化程度(P=0.042)是RFS的影响因素;OTUB1阴性及阳性中位RFS分别是18、19个月,差异无统计学意义(P>0.05)。COX多因素分析结果提示,分化程度(P=0.005)及TNM分期(P=0.006)是影响RFS的独立危险因素。结论 NSCLC中OTUB1 mRNA及蛋白表达均高于癌旁正常组织。在蛋白水平方面,OTUB1与PD-L1呈正相关。OTUB1表达与TNM分期相关。 | 陈秀红 李坤 靳爽 张中冕 | 2021 | 实用临床医药杂志2021，25，23： | 3 |
| 4 | Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets显示文摘Cancer immunotherapy harness the body's immune system to eliminate cancer,by using a broad panel of soluble and membrane proteins as therapeutic targets.Immunosuppression signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies,but because of repopulation of the membranevia intracellular organelles,targets must be eliminated in whole cells.Targeted protein degradation,as exemplified in proteolysis targeting chimera(PROTAC)studies,is a promising strategy for selective inhibition of target proteins.The recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer targets.Further studies on these molecules'modes of action,target-binding'warheads',lysosomal sorting signals,and linker design should facilitate their rational design.Modifications and derivatives may improve their cell-penetrating ability and thein vivo stability of these pro-drugs.These studies suggest the promise of alternative strategies for cancer immunotherapy,with the aim of achieving more potent and durable suppression of tumor growth.Here,the successes and limitations of antibody inhibitorsin cancer immunotherapy,as well as research progress on PROTAC-and lysosomal-dependent degradation of target proteins,are reviewed. | Yungang Wang Shouyan Deng Jie Xu | 2020 | Cancer Biology & Medicine2020，17，3： | 1 |
| 5 | 免疫检查点程序性细胞死亡蛋白配体-1翻译后修饰及其在免疫治疗中的应用前景显示文摘免疫检查点程序性细胞死亡蛋白配体-1(programmed cell death 1 ligand 1,PD-L1)是一种主要表达于肿瘤细胞表面的免疫抑制性分子,其可与T淋巴细胞表面的程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)结合,抑制T淋巴细胞的激活,发挥免疫抑制性功能。基于这一原理所开发的PD-1/PD-L1免疫阻断疗法,已在临床广泛应用于多种实体瘤的治疗,使诸多病人受益。与此同时,随着对PD-L1调控机制研究的深入,PD-L1的多种翻译后修饰形式陆续得到了鉴定,包括糖基化、磷酸化、泛素化和棕榈酰化等。研究表明,这些翻译后修饰过程可影响PD-L1的蛋白质稳定性与生理功能。因此,翻译后修饰成了PD-L1研究新的切入点。目前,PD-L1翻译后修饰靶向药物已在免疫治疗中展现出良好的应用前景。通过靶向PD-L1翻译后修饰过程,进而调控由PD-L1介导的肿瘤免疫逃逸,成了提高免疫治疗应答率的新思路和新策略。本文将对PD-L1翻译后修饰的研究进行系统总结,并陈述其在免疫治疗领域中的应用前景,希望为未来针对PD-L1翻译后修饰的研究提供理论支持。 | 崔宇琦 邹朝霞 高旭 | 2021 | 中国生物化学与分子生物学报2021，37，2： | 1 |
| 6 | PD-L1翻译后修饰的研究进展显示文摘高表达免疫检查点分子程序性死亡受体-配体1(programmed death ligand-1,PD-L1)是肿瘤细胞逃避机体免疫监视的重要途径。PD-L1的表达受到转录水平、翻译水平和翻译后修饰水平等的调控。近年来,PD-L1翻译后修饰逐渐成为PD-L1研究领域的热点。PD-L1的翻译后修饰包括糖基化、泛素化、磷酸化、棕榈酰化和乙酰化等,可影响PD-L1的稳定性及生物学功能。本文将对该领域的研究进展进行综述,以期为肿瘤免疫治疗研究提供新思路。 | 刘禹辰 刘丹 郑骏年 施明 | 2021 | 中国肿瘤临床2021，48，9： | 1 |
| 7 | Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors:mechanisms and strategies显示文摘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. | Liming Liao Huilin Xu Yuhan Zhao Xiaofeng Zheng | 2023 | Frontiers of Medicine2023，17，5： | 1 |
| 8 | 程序性细胞死亡蛋白1配体1(PD-L1)的翻译后修饰调控及其在肿瘤免疫治疗中的应用进展显示文摘程序性细胞死亡蛋白1配体1/程序性细胞死亡蛋白1(PD-L1/PD-1)免疫检查点是最有前景的肿瘤免疫治疗靶点之一。肿瘤等细胞表面过度表达的PD-L1通过与T细胞表面的PD-1结合,抑制T细胞活化,导致肿瘤免疫逃逸;靶向PD-1/PD-L1的治疗策略主要通过阻断二者结合,恢复免疫细胞对肿瘤的杀伤作用。肿瘤细胞中PD-L1的水平与功能受到多层次的调控,其中,PD-L1的翻译后修饰(PTM)近年来备受关注,主要包括糖基化、磷酸化、泛素化、乙酰化以及棕榈酰化修饰等,这些修饰方式能够影响PD-L1的稳定性、细胞内定位或功能,进而调控T细胞活化和肿瘤免疫,因而干预PD-L1的PTM亦可作为新的抗肿瘤免疫逃逸治疗手段。 | 苏媛媛 王秦豪 茹懿 董健 李霞 张正祥 | 2022 | 细胞与分子免疫学杂志2022，38，11： | 0 |
| 9 | 可溶性CD40配体对非霍奇金淋巴瘤raji细胞凋亡及PD-L1影响显示文摘目的分析可溶性CD40配体(sCD40L)对非霍奇金淋巴瘤(non-Hodgkinlymphoma,NHL)raji细胞增殖凋亡及凋亡死亡受体-配体1(PD-L1)的影响。方法实验组(加入2、4、6μg/mL的sCD40L)和对照组(未加sCD40L)作用NHL raji细胞24h,采用CCK-8法检测细胞增殖,流式细胞术AnnexinⅤFITC/PI法检测细胞凋亡,采用免疫细胞化学(immunocytochemistry,ICC)法检测PD-L1的表达。结果2、4、6μg/mL的sCD40L作用NHL raji细胞24h后,细胞增殖抑制率分别为(27.59±2.39)%、(41.96±1.76)%和(72.58±2.64)%,与对照组(11.86±1.53)%比较(线性F=1310.57,P<0.001),线性回归分量有统计学意义,说明存在相关关系即有线性趋势;线性偏差F=23.83,P<0.001,偏离线性回归分量有统计学意义,说明不是简单的线性关系。细胞凋亡率分别为(12.36±2.04)%、(28.61±3.73)%和(35.80±4.16)%,与对照组(3.53±0.37)%比较(线性F=215.94,P<0.001),线性回归分量有统计学意义,说明存在相关关系即有线性趋势;线性偏差F=2.41,P=0.152,偏离线性回归分量无统计学意义,说明是简单的线性关系。PD-L1表达分别为(81.00±3.00)%、(70.00±4.00)%和(12.00±2.00)%,与对照组(93.00±4.00)%比较(线性F=860.21,P<0.001),线性回归分量有统计学意义,说明存在相关关系即有线性趋势;线性偏差F=85.89,P<0.001,偏离线性回归分量有统计学意义,说明不是简单的线性关系。结论不同浓度的sCD40L可以抑制NHL raji细胞增殖、诱导凋亡,其机制可能与降低PD-L1表达有关。 | 封忠昕 陈琦 王季石 袁钟 彭志元 陈迪 张振东 | 2020 | 中华肿瘤防治杂志2020，27，24： | 0 |
| 10 | Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment显示文摘More and more in-depth studies have revealed that the occurrente and development of tumors depend on gene mutation and tumor heterogeneity.The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment(TME)heterogeneity.This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network.TME has resulted in novel therapeutic in terve ntions as a place beyond tumor beds.The malig nant can cer cells,tumor in filtrate immune cells,angiogenic vascular cells,lymphatic endothelial cells,cancer-associated fibroblastic cells,and the released factors including intracellular metabolites,hormonal signals and inflammatory mediators all contribute actively to cancer progression.Protein post-translational modification(PTM)is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis.Advances in quantitative transcriptomics,proteomics,and nuclease-based gene editing are now paving the global ways for exploring PTMs.In this review,we focus on recent developments in the PTM area and speculate on their importanee as a critical functional readout for the regulation of TME.A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies. | Wen Li Feifei Li Xia Zhang Huikuan Lin Chuan Xu | 2022 | Signal Transduction and Targeted Therapy2022，7，1： | 0 |
| 11 | 基于生物学分析构建及验证棕榈酰化相关酶长链非编码RNA的肝癌预后风险模型显示文摘目的·基于癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库筛选棕榈酰化相关长链非编码RNA(long non-coding RNA,lncRNA),构建肝癌预后风险模型。方法·从TCGA数据库中下载获取374例肝癌组织及50例正常组织样本的测序数据和对应的患者临床及预后资料,对肝癌组织与正常组织的差异锌指DHHC结构域(zinc finger aspartate-histidine-histidine-cysteine domain,ZDHHC)蛋白家族构建相关的lncRNA表达谱,并采用单因素回归分析筛选预后相关lncRNA,进一步通过最小绝对收缩和选择算子(least absolute shrinkage and selection operator,LASSO)回归算法构建预测模型;对模型预测的有效性进行验证,并分析模型高、低风险组与免疫功能的关系以及预测免疫治疗应答效果。结果·发现20个肝癌差异表达的ZDHHC,其中有656个lncRNA和差异ZDHHC有相关性(均P<0.05)。单因素COX分析筛选出22个lncRNA与肝癌的预后相关(HR为1.47~13.05,均P<0.05),LASSO回归分析纳入3个lncRNA构建风险模型,即风险模型分数=0.6626×AC026356.1+0.2139×AC026401.3+0.4056×POLH-AS1,模型中高风险组患者的总生存期(overall survival,OS)和无进展生存期(progression-free survival,PFS)明显低于低风险组患者(均P<0.05)。多因素COX回归分析显示,该模型作为风险因素是影响生存期的独立因素(HR=1.375,95%CI为1.208~1.566)。风险模型中高风险和低风险的免疫功能通路有明显差异,且高风险患者对免疫治疗的应答水平更低(P<0.05)。结论·使用基于棕榈酰化相关lncRNA表达的风险模型能够独立预测肝癌患者的生存期,为患者接受免疫治疗提供参考。 | 于莉 苏显都 张敏 李雅慧 王乐 | 2023 | 上海交通大学学报(医学版)2023，43，6： | 0 |
| 12 | 下调锌指棕榈酰基转移酶9表达抑制乳腺癌进展显示文摘目的探讨锌指棕榈酰基转移酶9(ZDHHC9)的表达对乳腺癌增殖、迁移侵袭和凋亡的影响以及其作用机制。方法利用癌症基因组图谱(TCGA)数据库分析乳腺癌中ZDHHC9的表达情况及与预后的关系。用慢病毒感染方式在HCC1937细胞、MCF7细胞、SKBR3细胞中敲低ZDHHC9,每种细胞分别设置一个对照组(shNC)和两个敲低实验组(sh1、sh2),通过细胞计数试剂盒(CCK-8)检测、细胞增殖检测(EdU)、平板克隆形成实验检测ZDHHC9对乳腺癌细胞增殖影响,通过划痕实验和小室细胞侵袭实验(Transwell)验证ZDHHC9对迁移和侵袭能力的影响,细胞流式分析检测ZDHHC9对细胞凋亡的影响。蛋白质免疫印迹法(Western blot)实验观察下调ZDHHC9对磷脂酰肌醇3-激酶/蛋白激酶B通路(PI3K/Akt)和细胞外调节蛋白激酶信号通路(ras/raf/MEK/Erk)的影响。采用t检验方法进行组间比较。结果TCGA数据库数据分析ZDHHC9在乳腺癌中高表达,且与不良预后相关。CCK-8实验表明下调ZDHHC9后乳腺癌细胞增殖被抑制(HCC1937-shNC比HCC1937-sh1:2.577±0.012比1.887±0.077,t=15.319,P<0.01;MCF7-shNC比MCF7-sh1:0.905±0.016比0.398±0.053,t=16.034,P<0.01;SKBR3-shNC比SKBR3-sh1:2.322±0.090比1.786±0.022,t=10.067,P<0.01);平板克隆形成实验提示敲低ZDHHC9后集落形成数量减少[HCC1937-shNC比HCC1937-sh1:(472.333±48.211)个比(362.667±43.108)个,t=7.637,P<0.01;MCF7-shNC比MCF7-sh1:(176.667±37.448)个比(79.667±27.227)个,t=3.639,P<0.01;SKBR3-shNC比SKBR3-sh1:(296.333±19.553)个比(210.667±11.676)个,t=6.515,P<0.01];划痕实验提示敲低ZDHHC9抑制乳腺癌细胞的迁移(HCC1937-shNC比HCC1937-sh1:0.536±0.046比0.235±0.010,t=10.969,P<0.01;SKBR3-shNC比SKBR3-sh1:0.429±0.021比0.231±0.060,t=5.381,P<0.01);Transwell侵袭实验表明下调ZDHHC9后乳腺癌细胞侵袭能力下降[HCC1937-shNC比HCC1937-sh1:(211.333±11.930)个比(73.667±5.508)个,t=18.146,P<0.01;SKBR3-shNC比SKBR3-sh1:(159.333±11.590)个比(45.333±7.024)个,t=14.570,P<0.01];流式细胞分析提示下调ZDHHC9导致细胞凋亡增加(HCC1937-shNC比HCC1937-sh1:0.121±0.007比0.157±0.004,t=6.634,P<0.01;SKBR3-shNC比SKBR3-sh1:0.124±0.0050.142±0.005,t=6.218,P<0.01);免疫印迹实验结果显示,敲低ZDHHC9抑制PI3K/Akt通路和ras/raf/MEK/Erk通路的激活被抑制[磷酸化蛋白激酶B(p-Akt)相对表达量:MCF7-shNC比MCF7-sh1:0.931±0.005比0.707±0.002,t=24.193,P<0.01;磷酸化细胞外信号调节激酶(p-ERK1/2)相对表达量:MCF7-shNC比MCF7-sh1:1.418±0.010比1.206±0.053,t=6.748,P<0.01]。结论敲低ZDHHC9抑制乳腺癌细胞的增殖、迁移和侵袭能力,促进细胞凋亡。 | 李孟轩 代引海 訾浩毅 王邑迪 张瑞 王廷 | 2023 | 中华实验外科杂志2023，40，4： | 0 |
| 13 | 免疫检查点程序性细胞死亡蛋白配体1翻译后修饰的研究进展显示文摘翻译后修饰是指多肽或蛋白质在翻译后所经历的共同加工过程,近年研究发现,程序性细胞死亡蛋白配体1(PD-L1)的翻译后存在多种修饰形式,例如糖基化、泛素化、磷酸化、甲基化、棕榈酰化和乙酰化等。翻译后修饰可通过影响PD-L1的蛋白质稳定性,促进PD-L1介导的肿瘤免疫逃逸,阻断PD-L1与程序性细胞死亡蛋白1(PD-1)的结合,增强自身免疫细胞对肿瘤细胞的杀伤功能,在PD-L1蛋白稳定性、易位和蛋白—蛋白相互作用中发挥重要作用,翻译后修饰的异常改变直接影响PD-L1介导的免疫抵抗。鉴于翻译后修饰机制通常是药物抑制肿瘤的治疗靶点,靶向PD-L1翻译后修饰可能是一种增强抗肿瘤免疫反应的新策略。 | 吴学雨 胡楠 张竞舟 洪义东 卞保祥 宋子琰 吴风雷 | 2022 | 山东医药2022，62，14： | 0 |
| 14 | 棕榈酰化转移酶9调控非小细胞肺癌增殖、迁移、侵袭及相关机制研究显示文摘目的:探讨棕榈酰化转移酶9(zinc finger DHHC-type containing 9,ZDHHC9)在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达及预后,及ZDHHC9对NSCLC细胞增殖、迁移和侵袭能力的影响及作用机制。方法:通过NCBI GEC数据库和基于基因表达水平值的交互式分析平台(gene expression profiling interactive analysis,GEPIA)数据库分析ZDHHC9在NSCLC中的表达及其与患者预后之间的关系。利用实时定量PCR(Real-time qPCR)检测正常支气管上皮细胞系(16HBE)及NSCLC细胞系(A549、H1299、H1703)的表达情况。在H1703和A549细胞系中敲降ZDHHC9,利用CCK-8实验检测细胞增殖能力,Transwell和划痕实验检测细胞迁移、侵袭能力,Western blot检测相关蛋白水平变化。结果:GEO和GEPIA数据库生物信息技术分析结果显示,ZDHHC9在NSCLC组织中较癌旁组织显著升高,并且ZDHHC9表达量与患者的无病生存率相关(P<0.01)。敲降ZDHHC9后,H1703和A549细胞增殖活力显著下降,同时侵袭和迁移能力受到抑制,并且敲降ZDHHC9降低NSCLC细胞脂肪酸合成关键酶的表达水平。结论:ZDHHC9可能通过调控NSCLC细胞脂肪酸合成促进NSCLC细胞的增殖、迁移和侵袭。 | 周容 高琛梓 赵廷枫 顾遥 王倩 | 2023 | 南京医科大学学报(自然科学版)2023，43，8： | 0 |
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