Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative bre...Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.展开更多
三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学...三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学作为高特异性及灵敏性的高通量研究方法,逐步成为目前应用热点。本文旨在从转化医学的角度分析蛋白质组学方法在TNBC诊疗研究中的临床应用价值。展开更多
Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its liga...Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.展开更多
Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and...Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and survival.Previous studies have demonstrated that triplenegative breast cancers(TNBC)may use glutamine as an extracellular nutrient source to generate lipids,proteins,and nucleic acids.1 Glutamine catabolism in cancer cells also contributes to the production of the antioxidant,glutathione(GSH),which is critical for redox homeostasis and for protection of cells from oxidative stress elicited by reactive oxygen species(ROS).2 Considering TNBC cell lines are often dependent on glutamine for growth and survival,we sought to determine whether targeting glutaminolysis with a small molecule inhibitor,CB-839,in combination with platinum-based chemotherapy drug,would elicit significant anti-tumor activity.展开更多
The molecular mechanism of triple-negative breast cancer（TNBC） remains unclear, and there has been no effective targeted therapy for it. A better understanding of the mechanisms of TNBC is urgently needed to identif...The molecular mechanism of triple-negative breast cancer（TNBC） remains unclear, and there has been no effective targeted therapy for it. A better understanding of the mechanisms of TNBC is urgently needed to identify new therapeutic targets. In this study, eight cases of premenopausal TNBC patients were collected, and a comparative proteomic analysis of their breast cancer tissues and matched paraneoplastic ones was performed via isobaric tags for relative and absolute quantitation（iTRAQ） technology coupled with two-dimensional liquid chromatography-tandem mass spectrumetry（2D LC-MS/MS）. The researches result in the identification of 1254 nonredundant proteins, of which 1243 proteins reached the strict quantitative standard. The quantitative comparison reveal that among the 214 proteins, 81 proteins significantly increased and 133 proteins decreased in TNBC tissues compared to corresponding ones in control. The Gene Ontology（GO） annotations and pathway analysis show their distributions in GO and the marked functions, as well as the closely related signal transduction pathways involved in extra cellular matrix （ECM）-receptor interaction, protein digestion and absorption, renin-angiotensin system, complement and coagulation cascades and focal adhesion. This pilot study will lay a foundation for further searching for therapeutic targets of TNBC and exploring the molecular mechanism, which can also be extended as a part of a large scale biomarker discovery plan.展开更多
目的探讨乙酰化STAT3对DIRAS2基因表达的调控及其在三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞增殖中的作用。方法通过数据库查询、Western blotting和qRT-PCR分析TNBC组织和细胞中DIRAS2和乙酰化STAT3的表达水平。选取TNB...目的探讨乙酰化STAT3对DIRAS2基因表达的调控及其在三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞增殖中的作用。方法通过数据库查询、Western blotting和qRT-PCR分析TNBC组织和细胞中DIRAS2和乙酰化STAT3的表达水平。选取TNBC细胞系MDA-MB-231和SUM159,通过慢病毒或质粒构建DIRAS2过表达及STAT3野生或Lys685位点突变的细胞株。利用CCK-8实验评估DIRAS2和STAT3乙酰化对TNBC细胞增殖的影响。应用Western blotting、焦磷酸测序、ChIP和IP技术研究乙酰化STAT3对DIRAS2表达的调控作用及机制。结果DIRAS2在TNBC组织和细胞中表达较低。焦磷酸测序分析发现,与正常乳腺上皮细胞相比,TNBC细胞中DIRAS2启动子区域的CpG岛甲基化水平升高,并促进癌细胞增殖。此外,TNBC细胞中STAT3的乙酰化程度增加,而DIRAS2启动子甲基化状态随着STAT3乙酰化的增加而发生改变。ChIP和IP实验表明,乙酰化STAT3可与DIRAS2启动子结合,而STAT3 Lys685位点突变会破坏STAT3与DNMT1的相互作用。结论在TNBC中,乙酰化STAT3通过招募DNMT1诱导DIRAS2基因启动子甲基化,从而导致DIRAS2表达缺失和癌细胞增殖。展开更多
目的:通过检测三阴性乳腺癌(triple-negative breast cancer,TNBC)组织中肿瘤相关中性粒细胞(tumor-associated neutrophils,TANs)浸润密度及程序性死亡配体-1(PD-L1)的表达情况来分析二者的相关性,并探究其临床意义。方法:选取141例我...目的:通过检测三阴性乳腺癌(triple-negative breast cancer,TNBC)组织中肿瘤相关中性粒细胞(tumor-associated neutrophils,TANs)浸润密度及程序性死亡配体-1(PD-L1)的表达情况来分析二者的相关性,并探究其临床意义。方法:选取141例我院三阴性乳腺癌患者组织标本,使用抗体CD66b作为TANs的标记物,通过免疫组织化学法检测TNBC肿瘤组织内TANs浸润和PD-L1表达的情况。采用Pearson积差相关或Spearman等级相关分别分析TANs浸润密度和PD-L1表达与临床病理特征的相关性,以及TNBC肿瘤组织内TANs浸润密度与PD-L1阳性表达之间的相关性;采用Kaplan-Meier曲线对TNBC患者进行生存分析。结果:TANs高浸润密度与高Ki67增殖指数、高组织学分级以及淋巴结转移均呈正相关(P<0.05)。PD-L1表达与高Ki67增殖指数及高组织学分级均呈正相关(P<0.05)。TNBC中TANs的浸润密度与PD-L1阳性表达呈正相关(P<0.05)。生存分析显示,TANs浸润密度和PD-L1表达均与TNBC患者的无进展生存期呈负相关(P<0.05)。结论:TNBC肿瘤组织内TANs浸润密度和PD-L1表达与多项临床病理特征以及不良预后密切相关,这提示TANs及PD-L1可作为TNBC预后评估的重要指标,并为探索TNBC免疫治疗潜在靶点提供研究依据。展开更多
三阴性乳腺癌(TNBC)是一种侵袭性乳腺癌亚型,通常以缺乏雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体-2 (HER2)为特征,约占所有乳腺癌的15%~20%。与其他分子表型相比,TNBC通常与高恶性和不良预后相关。在DNA水平上整合组学知识...三阴性乳腺癌(TNBC)是一种侵袭性乳腺癌亚型,通常以缺乏雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体-2 (HER2)为特征,约占所有乳腺癌的15%~20%。与其他分子表型相比,TNBC通常与高恶性和不良预后相关。在DNA水平上整合组学知识,进一步扩大了对乳腺癌的生物学认识,这是临床上三阴性肿瘤的迫切需求。由于缺乏明确的靶点和有限的治疗干预措施,细胞毒性药物在过去几十年中一直是治疗的主要手段。然而,最近的发展表明,TNBC具有特殊的分子分类和生物标志物,这为从基本的细胞毒性化疗发展到扩大靶向治疗领域提供了可能性。随着检测技术的不断发展和对TNBC分子亚型研究的不断深入,出现了针对免疫检查点和不同靶点的药物,如抗体–药物偶联物等。这些疗法为TNBC的治疗提供了新的希望。本文在对TNBC进行分析和分类的基础上,总结了免疫治疗与新的治疗组合,为今后TNBC的精准治疗提供参考。Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is typically characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) and accounts for approximately 15% to 20% of all breast cancers. TNBC is often associated with high malignancy and poor prognosis compared to other molecular phenotypes. Integrating omics knowledge at the DNA level further expands the biological understanding of breast cancer, which is urgently needed in the clinical setting of triple-negative tumors. Due to the lack of clear targets and limited therapeutic interventions, cytotoxic drugs have been the mainstay of treatment in the past decades. However, recent developments have shown that TNBC has a specific molecular classification and biomarkers, which opens up the possibility of moving from basic cytotoxic chemotherapy to expanding the field of targeted therapy. With the continuous development of detection technology and the deepening of research on the molecular subtypes of TNBC, drugs targeting immune checkpoints and different targets, such as antibody-drug conjugates, have emerged. These therapies provide new hope for the treatment of TNBC. Based on the analysis and classification of TNBC, this article summarizes the immunotherapy and new treatment combinations, so as to provide reference for the precise treatment of TNBC in the future.展开更多
基金the projects of the National Key Research and Development Program(No.2021YFA0716702)the National Natural Science Foundation of China(Nos.61805122,22022404 and 22074050)+5 种基金Green Industry Science and Technology Leading Project of Hubei University of Technology(No.XJ2021003301)the National Natural Science Foundation of Hubei Province(No.2022CFA033)supported by Chinese Society of Clinical Oncology(CSCO)supported by Jiangsu Hengrui Cancer Research Foundation(No.YHR2019–0325)supported by the Fundamental Research Funds for the Central Universities(No.CCNU22QN007)supported by the Opening Fund from the Jiangsu Key Laboratory of Medical Optics,Suzhou Institute of Biomedical Engineering and Technology(No.JKLMO202203)supported by the Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science,MO(No.M2022–5).
文摘Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.
文摘三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学作为高特异性及灵敏性的高通量研究方法,逐步成为目前应用热点。本文旨在从转化医学的角度分析蛋白质组学方法在TNBC诊疗研究中的临床应用价值。
基金supported by the Department of Science and Technology(Nano Mission:DST/NM/NT/2018/105(G),SERB:EMR/2017/000992/HS&EMR/2017/001183)Council of Scientific and Industrial Research[(FBR Project No.31-2(274)2020e21),HCP-40],Govt.of India.
文摘Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.
基金The study was supported by Ovarian Cancer Research Alliance and the Johns Hopkins-Allegheny Health Network Cancer Research Fund,United States.
文摘Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and survival.Previous studies have demonstrated that triplenegative breast cancers(TNBC)may use glutamine as an extracellular nutrient source to generate lipids,proteins,and nucleic acids.1 Glutamine catabolism in cancer cells also contributes to the production of the antioxidant,glutathione(GSH),which is critical for redox homeostasis and for protection of cells from oxidative stress elicited by reactive oxygen species(ROS).2 Considering TNBC cell lines are often dependent on glutamine for growth and survival,we sought to determine whether targeting glutaminolysis with a small molecule inhibitor,CB-839,in combination with platinum-based chemotherapy drug,would elicit significant anti-tumor activity.
基金Supported by the National Natural Science Foundation of China（No.81041098）.
文摘The molecular mechanism of triple-negative breast cancer（TNBC） remains unclear, and there has been no effective targeted therapy for it. A better understanding of the mechanisms of TNBC is urgently needed to identify new therapeutic targets. In this study, eight cases of premenopausal TNBC patients were collected, and a comparative proteomic analysis of their breast cancer tissues and matched paraneoplastic ones was performed via isobaric tags for relative and absolute quantitation（iTRAQ） technology coupled with two-dimensional liquid chromatography-tandem mass spectrumetry（2D LC-MS/MS）. The researches result in the identification of 1254 nonredundant proteins, of which 1243 proteins reached the strict quantitative standard. The quantitative comparison reveal that among the 214 proteins, 81 proteins significantly increased and 133 proteins decreased in TNBC tissues compared to corresponding ones in control. The Gene Ontology（GO） annotations and pathway analysis show their distributions in GO and the marked functions, as well as the closely related signal transduction pathways involved in extra cellular matrix （ECM）-receptor interaction, protein digestion and absorption, renin-angiotensin system, complement and coagulation cascades and focal adhesion. This pilot study will lay a foundation for further searching for therapeutic targets of TNBC and exploring the molecular mechanism, which can also be extended as a part of a large scale biomarker discovery plan.
文摘目的:通过检测三阴性乳腺癌(triple-negative breast cancer,TNBC)组织中肿瘤相关中性粒细胞(tumor-associated neutrophils,TANs)浸润密度及程序性死亡配体-1(PD-L1)的表达情况来分析二者的相关性,并探究其临床意义。方法:选取141例我院三阴性乳腺癌患者组织标本,使用抗体CD66b作为TANs的标记物,通过免疫组织化学法检测TNBC肿瘤组织内TANs浸润和PD-L1表达的情况。采用Pearson积差相关或Spearman等级相关分别分析TANs浸润密度和PD-L1表达与临床病理特征的相关性,以及TNBC肿瘤组织内TANs浸润密度与PD-L1阳性表达之间的相关性;采用Kaplan-Meier曲线对TNBC患者进行生存分析。结果:TANs高浸润密度与高Ki67增殖指数、高组织学分级以及淋巴结转移均呈正相关(P<0.05)。PD-L1表达与高Ki67增殖指数及高组织学分级均呈正相关(P<0.05)。TNBC中TANs的浸润密度与PD-L1阳性表达呈正相关(P<0.05)。生存分析显示,TANs浸润密度和PD-L1表达均与TNBC患者的无进展生存期呈负相关(P<0.05)。结论:TNBC肿瘤组织内TANs浸润密度和PD-L1表达与多项临床病理特征以及不良预后密切相关,这提示TANs及PD-L1可作为TNBC预后评估的重要指标,并为探索TNBC免疫治疗潜在靶点提供研究依据。
文摘三阴性乳腺癌(TNBC)是一种侵袭性乳腺癌亚型,通常以缺乏雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体-2 (HER2)为特征,约占所有乳腺癌的15%~20%。与其他分子表型相比,TNBC通常与高恶性和不良预后相关。在DNA水平上整合组学知识,进一步扩大了对乳腺癌的生物学认识,这是临床上三阴性肿瘤的迫切需求。由于缺乏明确的靶点和有限的治疗干预措施,细胞毒性药物在过去几十年中一直是治疗的主要手段。然而,最近的发展表明,TNBC具有特殊的分子分类和生物标志物,这为从基本的细胞毒性化疗发展到扩大靶向治疗领域提供了可能性。随着检测技术的不断发展和对TNBC分子亚型研究的不断深入,出现了针对免疫检查点和不同靶点的药物,如抗体–药物偶联物等。这些疗法为TNBC的治疗提供了新的希望。本文在对TNBC进行分析和分类的基础上,总结了免疫治疗与新的治疗组合,为今后TNBC的精准治疗提供参考。Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is typically characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) and accounts for approximately 15% to 20% of all breast cancers. TNBC is often associated with high malignancy and poor prognosis compared to other molecular phenotypes. Integrating omics knowledge at the DNA level further expands the biological understanding of breast cancer, which is urgently needed in the clinical setting of triple-negative tumors. Due to the lack of clear targets and limited therapeutic interventions, cytotoxic drugs have been the mainstay of treatment in the past decades. However, recent developments have shown that TNBC has a specific molecular classification and biomarkers, which opens up the possibility of moving from basic cytotoxic chemotherapy to expanding the field of targeted therapy. With the continuous development of detection technology and the deepening of research on the molecular subtypes of TNBC, drugs targeting immune checkpoints and different targets, such as antibody-drug conjugates, have emerged. These therapies provide new hope for the treatment of TNBC. Based on the analysis and classification of TNBC, this article summarizes the immunotherapy and new treatment combinations, so as to provide reference for the precise treatment of TNBC in the future.
