髓样抑制细胞在肿瘤生物学中作用的研究进展

髓样抑制细胞(myeloid-derived suppressor cells,MDSCs)是存在于荷瘤小鼠及肿瘤患者体内、具有免疫抑制功能的细胞群。它由髓系来源的未分化成熟的具有异质性的细胞组成,其中包括树突状细胞、巨噬细胞和粒细胞等。肿瘤细胞分泌的各种因子能诱导MDSCs的产生、运动及活化。荷瘤小鼠来源的MDSCs主要表达CD11b+Gr1+,而肿瘤患者来源的MDSCs主要表达CD11b+CD14-。在荷瘤小鼠骨髓、脾脏和外周血及肿瘤患者的外周血中MDSCs水平升高。MDSCs通过抑制机体免疫功能和促进新生血管生成等机制参与肿瘤的生长及向远处转移。抑制体内MDSCs的功能和降低其数量有助于恢复机体识别、杀伤肿瘤细胞的能力,并提高药物疗效。本文对MDSCs在肿瘤领域的最新研究进展进行综述。     

MDSCs与肿瘤免疫逃逸

髓源抑制性细胞(myeloidderived suppressor cells, MDSCs)是一群异质性细胞,来源于骨髓祖细胞和未成熟髓细胞(immature myeloid cells, IMCs),是树突状细胞（dendritic cells, DCs）、巨噬细胞和（或）粒细胞的前体。在荷瘤小鼠的血液、脾脏和肿瘤组织及肿瘤患者的外周血和肿瘤组织存在大量MDSCs的扩增。MDSCs可以通过多种途径抑制机体的获得性和天然抗肿瘤免疫,使肿瘤细胞逃避机体的免疫监视和攻击,促进肿瘤发展。MDSCs首先从骨髓募集到外周,并在外周被激活后才能发挥抗肿瘤免疫抑制功能,肿瘤来源的慢性炎症相关的一系列因子在介导MDSCs的募集和活化中起关键作用。当前靶向MDSCs的抗肿瘤治疗取得了一定的进展,但MDSCs从发现到现在仅仅经历了10年左右的时间,该领域中许多的未知尚需要大量的基础和临床研究来阐明。本文主要介绍MDSCs的特征及其亚群、MDSCs的募集和活化、MDSCs介导免疫逃逸的机制及当前靶向MDSCs的抗肿瘤治疗策略,以期为从事该领域的研究工作者提供参考。     

髓源性抑制细胞在肺癌中的研究进展

髓源性抑制细胞(Myeloid-derived suppressor cells,MDSCs)是一群来自骨髓不成熟的异质性细胞,表型及成分复杂,在肿瘤微环境中发挥免疫抑制功能,并主要抑制T细胞免疫应答.在肺癌的发生、发展过程中,多种异常表达的细胞因子促进MDSCs增殖与激活,MDSCs活化后参与形成抑制性肿瘤免疫微环境,从而促进肿瘤细胞生长.监测MDSCs的数量与功能变化对评估肺癌的预后有重要意义.一系列针对MDSCs的干预措施在肺癌治疗中获得了重大进展,也为肺部原发及转移瘤的预防带来了希望.     

骨髓源性抑制细胞在肿瘤免疫治疗中的研究进展及与肺癌预后的关系

免疫治疗是肺癌新兴治疗方法,其疗效受肿瘤免疫微环境（tumor immune microenvironment,TIME）影响。骨髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是免疫微环境的主要免疫抑制细胞,在肿瘤的发生、发展、侵袭和转移过程中起关键作用。近年来,探索克服MDSCs的免疫抑制,从而增强抗肿瘤治疗疗效的研究已经成为研究热点。在这篇综述中,我们讨论了靶向MDSCs以及与ICI联合治疗的进展,并总结了MDSCs对肺癌患者预后的影响。     

IL-6 通过诱导SOCS3表达缺失促进乳腺癌MDSCs 浸润和免疫抑制活性

目的：探讨髓系来源抑制细胞（myeloid-derived suppressor cells,MDSCs）通过IL-6 诱导STAT3/IDO信号通路活化对T细胞的免疫抑制作用及其分子机制。方法：收集天津医科大学肿瘤医院2015 年11 月至2016 年2 月收治的20 例乳腺癌患者肿瘤组织及其癌旁组织和40 例健康供者的外周血样本。免疫磁珠技术分选肿瘤组织中的CD33+和健康供者外周血中的CD33+和CD14+细胞,CD33+体外与乳腺癌细胞系MDA-MB-231 共孵诱导MDSCs生成。流式细胞术检测表型为CD45+CD13+CD33+CD14-CD15-的MDSCs 比例,Western blotting 检测细胞因子信号转导抑制因子1(suppressors of cytokine signalling 1,SOCS1)、SOCS3、JAK1、JAK2、TYK2、STAT1、STAT3 及其磷酸化水平,qRT-PCR 检测IL-6、SOCS1-3 的表达水平,CCK-8 法检测T 细胞增殖情况,Annexin V检测T 细胞凋亡,ELISA 检测T 细胞分泌的IL-10 和IFN-γ。结果：20 例乳腺癌组织中均有不同程度的MDSCs浸润（15.3%~58.1%）,平均为（29.82±11.46）%;IL-6high组MDSCs浸润比例明显高于IL-6low组[ （13.75±3.44）% vs（4.31±1.50）%,P<0.05],且IL-6 表达与MDSCs浸润呈正相关（R2=0.4399,P<0.01)。体外实验发现肿瘤源性IL-6 明显促进体外MDSCs的生成和免疫抑制活性,该过程可被IL-6 信号的阻断所逆转（P<0.05）;同样发现在体外诱导的MDSCs中SOCS3 表达缺失,阻断IL-6 后,以上过程被明显抑制（P< 0.05）。结论：乳腺癌来源的IL-6 刺激MDSCs中JAK/STAT信号通路的持续活化和SOCS3 的表达缺失,进而促进MDSCs的浸润、生成和免疫活性。因此IL-6 信号通路可以作为削弱MDSCs生成和逆转MDSCs活性的治疗靶点。     

乳酸脱氢酶与肿瘤免疫代谢研究进展

不同免疫细胞亚群的代谢特征有所不同,抗肿瘤免疫细胞主要以有氧酵解和谷氨酰胺分解代谢提供代谢的物质与能量,而促进肿瘤发生和进展的抑制性免疫细胞亚群可利用肿瘤细胞代谢产物通过脂肪酸代谢等途径获取能量及中间产物。乳酸作为糖酵解途径的重要产物,直接或间接地影响肿瘤生物学行为,参与肿瘤免疫微环境调控。乳酸代谢的关键酶乳酸脱氢酶（LDH）常在肿瘤组织中高表达,是肿瘤微环境中连接各种免疫细胞代谢的关键酶之一,可激活某些信号传导途径和调控免疫应答参与肿瘤发生、发展。LDH水平升高主要由于肿瘤糖酵解活性增加和肿瘤缺氧坏死引起,其为免疫抑制性微环境的重要驱动者,LDH水平在一定程度上反映并可用于肿瘤糖酵解活性和免疫代谢状态的评估。本文对LDH与T淋巴细胞、巨噬细胞、树突状细胞等免疫细胞的代谢相关研究进行综述,旨在探究其在恶性肿瘤预后评估、抗肿瘤治疗尤其是免疫治疗疗效预测及监测中的可能应用。     

环氧化酶-2通过影响髓源抑制性细胞增殖及活化参与肝细胞肿瘤进展

目的:以COX2-PGE2通路为靶标,探讨其调控髓源抑制性细胞（myeloid-derived suppressor cell,MDSC）增殖及活化,进而影响肝细胞肿瘤（hepatocelluar carcinoma,HCC）进展的可能机制。方法:建立小鼠肝细胞肿瘤模型,利用流式细胞术分析外周血及脾脏组织中的MDSC比例,CFSE标记法分析肿瘤浸润MDSCs对T淋巴细胞增殖的影响,ELISA检测肿瘤组织体外培养上清中PGE2水平,Western blot检测肿瘤组织中COX-2表达,最终腹腔注射COX2-PGE2通路的小分子抑制剂吲哚美辛,证实该通路在调控MDSCs增殖活化,进而影响肿瘤进展过程中具有重要作用。结果:随着HCC的进展,小鼠外周血及脾脏中MDSC比例逐渐升高,其对T淋巴细胞增殖的抑制作用,即免疫抑制功能显著增加;肿瘤组织COX-2及PGE2表达水平较正常肝脏显著升高,腹腔注射吲哚美辛能够有效抑制肿瘤生长;过继回输MDSC则在一定程度上降低吲哚美辛的肿瘤抑制作用。结论:HCC发展过程中,肿瘤细胞通过COX2-PGE2通路活化MDSC,促进肿瘤进展。COX2-PGE2通路抑制剂吲哚美辛可通过抑制MDSC介导的免疫抑制作用,减缓肿瘤进程。     

三氧化二砷负向调控MDSC的肿瘤免疫抑制功能

目的:研究三氧化二砷(arsenic trioxide,As2O3)是否通过抑制髓系来源抑制性细胞(myeloid-derived suppressor cells,MDSCs)负向调控MDSCs诱导的肿瘤免疫耐受作用.方法:C57BL/6小鼠皮下注射黑素瘤B16细胞和肝癌H22细胞构建移植瘤模型,As2O3处理,观察移植瘤生长情况,流式细胞术检测荷瘤小鼠脾脏内MDSCs和其他免疫细胞的免疫表型,流式细胞术检测2 μmol/L As2O3对B16模型小鼠来源的MDSCs分化的影响.取B16模型小鼠随机分为As2O3处理及对照组,混合淋巴细胞反应检测MDSCs对T细胞免疫抑制活性的改变,ELISA检测B16模型小鼠血清及MDSCs培养上清中TNF-α、IL-10的水平.结果:As2O3抑制B16和H22模型鼠的肿瘤生长,延长B16模型小鼠的生存期,并可显著下调小鼠脾脏内MDSCs的比例.体外经2 μmol/L As2O3处理5d后,B16模型小鼠来源的MDSCs中成熟DCs(CD11c+ CD40+)的比例较对照组显著升高[(27.38±4.57)％ vs (17.44±4.51)％,P=0.0078];As2O3组来源的MDSCs对T细胞的免疫抑制活性明显低于对照组(P =0.016);As2O3组小鼠血清及MDSCs培养上清中TNF-α(F=5.78,P=0.014)和IL-10(F=17.83,P=0.045)的含量均较对照组显著降低.结论:As2O3可通过诱导MDSCs向成熟表型分化、下调其免疫抑制活性等,负调控MDSCs的肿瘤免疫抑制功能.     

髓系来源的抑制性细胞在小鼠H22原位种植性肝癌中的表达及其意义

目的:比较小鼠H22原位种植性肝癌模型中髓系来源的抑制性细胞（MDSCs）和调节性T细胞（Tregs）的表达，确定主要的免疫抑制性细胞。并探讨主要免疫抑制性细胞在小鼠H22原位种植性肝癌模型中的意义。方法:建立小鼠H22原位种植性肝癌模型，用流式细胞术的方法比较外周血、脾脏、肿瘤组织中MDSCs、Tregs的比例。分析MDSCs与CD4+T细胞、CD8+T细胞、NK细胞、NKT细胞的相关性。通过脾脏切除的方法下调MDSCs的表达，观察对肿瘤存活的影响。结果:MDSCs的比例无论在外周血、脾脏还是肿瘤组织中都显著高于Tregs。MDSCs的比例与CD4+T细胞、CD8+T细胞、NK细胞、NKT细胞呈负相关。下调MDSCs的比例可以显著延长小鼠存活期。结论:小鼠H22原位种植性肝癌中主要的免疫抑制性细胞是MDSCs。MDSCs的高表达预示着不良的小鼠存活期。     

肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。     

髓系抑制性细胞与肿瘤

髓系抑制性细胞(MDSC)是一群髓系来源具有抑制功能的天然免疫细胞,在肿瘤进展中发挥负向免疫调控作用.MDSC具有强大的抑制功能及显著的异质性,通过多种机制调控固有免疫及适应性免疫系统,发挥促肿瘤作用,同时可通过非免疫机制促进肿瘤血管生成及肿瘤转移等.近年来对其分化、增殖、抑制功能等的研究日趋成熟,由此衍生的靶向针对MDSC的肿瘤免疫治疗研究将为肿瘤疫苗的增效及肿瘤的治疗等带来新的希望.     

MDSCs的功能研究新发现

Myeloid derived suppressor cells（MDSCs）is a crowd of cells, which can suppress the immune response, mainly by inhibiting T cells function, as a result, contributing to the genesis and development of disease. With the increasing importance of MDSCs as targets for treatment of cancer, more and more people have given considerable attention to it, and have achieved certain results. In this paper we reviewed the MDSCs immunosuppressive mechanism, and the role of MDSCs as potential targets in animal experiments, as well as in clinical researches, aiming at offering new insights into the treatment of malignant tumor.     

髓源性抑制细胞联合免疫检查点抑制剂抗肿瘤治疗的研究进展CSCD

免疫检查点抑制剂(ICI)可通过恢复T细胞对肿瘤细胞的识别和损伤功能来增强原有的抗肿瘤免疫应答。ICI已被批准用于黑色素瘤、非小细胞肺癌(NSCLC)和肾细胞癌等多种肿瘤的治疗。然而,许多患者对免疫治疗没有反应。其中部分原因是由髓源性抑制细胞(MDSCs)介导的。这种异质的未成熟骨髓细胞群可以强烈抑制T细胞和NK细胞的抗肿瘤活性并刺激调节性T细胞(Treg)产生免疫抑制,导致肿瘤进展。MDSCs可以促进患者对免疫检查点抑制的耐药。越来越多的证据表明MDSCs在肿瘤患者中的比例和免疫抑制功能可用于治疗反应的预测。本综述重点介绍了MDSCs在免疫检查点抑制中的作用,并提供了MDSCs与ICI靶向联合治疗的策略,以提高后者在肿瘤治疗中的疗效。     

The restoration of myeloid-derived suppressor cells as functional antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment

Myeloid-derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen-presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down-regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all-trans-retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand-loaded, ATRA-treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA-mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.     

髓源性抑制细胞在构筑转移前微环境促肿瘤转移中的作用

肿瘤细胞持续存活是肿瘤转移过程中的主要限速环节.与肿瘤微环境类似,转移前器官的局部微环境(转移前微环境)为肿瘤细胞的存活提供了适宜的环境,是肿瘤细胞在远端器官持续存活、增殖的重要条件.髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是这一环境中的关键成分,其构筑的促增殖、炎症、免疫抑制及血管重塑的转移前微环境在肿瘤细胞的种殖、转移灶的形成过程中具有重要作用,是抗肿瘤转移治疗的潜在靶点.该研究主要介绍MDSCs构筑转移前微环境的机制及相关信号通路,为干预转移前微环境的抗肿瘤转移研究提供参考.     

髓源性抑制细胞在肿瘤发生发展中的作用

髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是一组异质细胞,在肿瘤相关免疫抑制中起关键作用.MDSCs通过免疫抑制作用,使肿瘤逃避免疫监控.肿瘤组织中MDSCs的浸润与患者预后不良及治疗的抵抗密切相关.MDSCs在转移中发挥重要作用,但MDSCs在远处器官建立转移前微环...     

The immunobiology of myeloid-derived suppressor cells in cancer

The tumor microenvironment is a complex and heterogeneous milieu in which multiple interactions occur between tumor and host cells. Immunosuppressive cells which are present in this microenvironment, such as regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), play an important role in tumor progression, via down-regulation of antitumor responses. MDSCs represent a heterogeneous group of cells originated from the myeloid lineage that are in the immature state. These cells markedly accumulate under pathologic conditions, such as cancer, infection, and inflammation, and use various mechanisms to inhibit both adaptive and innate immune responses. These immunosuppressive mechanisms include deprivation of T cells from essential amino acids, induction of oxidative stress, interference with viability and trafficking of T cells, induction of immunosuppressive cells, and finally polarizing immunity toward a tumor-promoting type 2 phenotype. In addition to suppression of antitumor immune responses, MDSCs can also enhance the tumor metastasis and angiogenesis. Previous studies have shown that increased frequency of MDSCs is related to the tumor progression. Moreover, various drugs that directly target these cells or reverse their suppressive activity can improve antitumor immune responses as well as increase the efficacy of immunotherapeutic intervention. In this review, we will first discuss on the immunobiology of MDSCs in an attempt to find the role of these cells in tumor progression and then discuss about therapeutic approaches to target these cells.     

Adjuvant effects of formalin‐inactivated HSV through activation of dendritic cells and inactivation of myeloid‐derived suppressor cells in cancer immunotherapy

Use of adequate adjuvant is necessary for induction of effective antitumor immune responses. To develop an effective adjuvant for cancer immunotherapy, we selected formalin‐inactivated (f)‐HSV as an adjuvant component, and analyzed the mechanisms underlying its adjuvant effects. First, we found that f‐HSV can induce the tumor antigen‐specific CTLs by enhancing antigen cross‐presentation by dendritic cells (DCs), mainly through TLR2, but not TLR9. Next, f‐HSV was also found to prevent the accumulation of myeloid‐derived suppressor cells (MDSCs). We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors, vascular endothelial growth factor (VEGF)‐A and neuropilin‐1 (NRP‐1), a co‐receptor for VEGF receptor‐2 (VEGFR‐2). Interestingly, the transmembrane‐type NRP‐1 on B cells changed to soluble‐type NRP‐1 (sNRP‐1) by f‐HSV treatment. We further showed that the sNRP‐1 and VEGF‐A secreted from B cells by f‐HSV treatment could abrogate the immunosuppressive ability of MDSCs. These results suggest that f‐HSV can enhance antitumor immune responses as an adjuvant, not only through activation of DCs, but also inactivation of MDSCs via B cells.     

TGF-β Enhances the Anti-inflammatory Effect of Tumor- Infiltrating CD33+11b+HLA-DR Myeloid-Derived Suppressor Cells in Gastric Cancer: A Possible Relation to MicroRNA-494

Background: Accumulation of myeloid-derived suppressor cells (MDSCs) constitutes a key mechanism of tumor immune evasion in gastric cancer (GC). Therefore, searching for more accurate prognostic factors affecting their immunosuppressive role has become a growing interest in cancer immunotherapy research. Increased expression of microRNA-494 was noticed in MDSCs from tumor-bearing mice, suggesting another new therapeutic objective for cancer treatment. It was also discovered that tumor-derived transforming growth factor beta (TGF-β) is responsible for the up-regulation of microRNA-494 in MDSCs. The purpose of this study was to address the effect of recombinant (rTGF-β) on the anti-inflammatory activity of MDSCs in GC and its possible association with micro-RNA-494 expression in tumor tissue. Methods: Freshly obtained GC tumor tissue samples and peripheral blood were used for isolation of CD33+11b+HLADR- MDSCs cells from 40 GC patients and 31 corresponding controls using flow cytometry. MDSCs were co-cultured with isolated autologous T cells to assess proliferation and cytokine production in the presence and absence of rTGF-β. Real-time PCR and Enzyme linked immunosorbent assay were used to evaluate tumor expression of miRNA-494 and TGF-β respectively. Results: Results showed that rTGF-β markedly increased the suppressive ability of tumor MDSCs on proliferation of autologous T cells and interferon gamma production. However, no inhibitory effect was observed for MDSCs from circulation. In addition, infiltration of MDSCs in tumors is associated with the prognosis of GC. MiRNA-494 was also extensively expressed in tumor samples with a significant correlation to MDSCs. Conclusion: These results indicate that tumor-derived MDSCs but not circulatory MDSCs have an immunosuppressive effect on T cells, potentially involving TGF-β mediated stimulation.  Results also suggest a role for miRNA-494 in GC progression. Therefore, control of TGF-β and miRNA-494 may be used as a treatment strategy to downregulate the immunosuppressive effect of MDSCs.     

Dual roles of myeloid-derived suppressor cells induced by Toll-like receptor signaling in cancer

Myeloid-derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment (TME), and are the main mediators of tumor-induced immunosuppression. Recent studies have reported that the survival, differentiation and immunosuppressive activity of MDSCs are affected by the Toll-like receptor (TLR) signaling pathway. However, the regulatory effect of TLR signaling on MDSCs remains controversial. TLR-induced MDSC can acquire different immunosuppressive activities to influence the immune response that can be either beneficial or detrimental to cancer immunotherapy. The present review summarizes the effects of TLR signals on the number, phenotype and inhibitory activity of MDSCs, and their role in cancer immunotherapy, which cannot be ignored if effective cancer immunotherapies are to be developed for the immunosuppression of the TME.