髓系来源的抑制性细胞在肿瘤进展过程中的研究

进展性肿瘤显著的特性是逃避机体免疫系统的监视、躲避免疫系统的杀伤、抑制自体免疫系统。肿瘤在进展过程中一群髓系来源的抑制性细胞（MDSC）在肿瘤微环境、引流区淋巴结大量聚集,其能够促进肿瘤的发展同时抑制机体的免疫作用。其机制概括为：髓系细胞向正常树突状细胞或巨噬细胞的分化受阻,分泌促进肿瘤生长的细胞因子,参与肿瘤血管的形成,诱导调节性T淋巴细胞（Treg）的产生,从而抑制了T淋巴细胞的抗肿瘤作用。     

Zbtb1基因促进小鼠淋巴细胞发育并抑制髓系细胞产生

目的探讨Zbtb1基因促进淋巴细胞发育的机制和对髓系细胞产生的影响。方法采用逆转录病毒在造血干细胞中过表达特定基因,并于OP9/OP-DL1系统中进行体外分化。结果 Zbtb1野生型造血干细胞在OP9/OP-DL1系统中可分化为B/T细胞,Zbtb1突变体(Scan T)造血干细胞在上述系统中淋巴细胞分化受阻,在淋巴细胞分化条件下均发育为髓系细胞。在Scan T突变体的造血干细胞中过表达抗凋亡基因Bcl2仅能部分恢复T细胞的早期发育,却不能改变其髓系细胞发育倾向。此外,在野生型的造血干细胞中过表达Zbtb1基因可在体外髓系诱导条件下抑制髓系细胞的发育。结论 Zbtb1基因可能通过抑制凋亡促进淋巴细胞发育,同时通过调控Csf1r的转录水平抑制髓系细胞分化。     

肿瘤微环境中髓系来源抑制细胞对T细胞免疫活性抑制的分子机制

髓系来源抑制细胞(MDSC)根据其起源和功能而命名,由巨噬细胞、树突状细胞(DC)及粒细胞等细胞的前体细胞组成。肿瘤免疫逃逸与肿瘤微环境中MDSC介导的抗肿瘤免疫抑制相关,肿瘤微环境中的MDSC主要通过抑制T细胞的免疫活性来发挥免疫抑制作用。根据MDSC与T细胞之间的接触方式,肿瘤微环境中的MDSC抑制T细胞免疫功能的分子机制可分为直接抑制和间接抑制两类,其中MDSC通过产生细胞因子影响T细胞功能和细胞之间膜受体配体相互作用发挥抑制T细胞功能的方式为直接抑制,而MDSC通过影响T细胞代谢从而影响T细胞功能及通过其他细胞发挥抑制T细胞功能的方式为间接抑制。制定针对MDSC的治疗策略时,需综合考虑上述多种分子机制共存的可能性。     

急性髓细胞白血病患者外周血淋巴细胞亚群的特征及临床意义

目的通过检测急性髓细胞白血病患者外周血各淋巴细胞亚群的分布,探讨该类患者免疫功能状况。方法通过流式细胞术检测健康对照组(n=20)、急性髓细胞白血病初发患者(n=31)及完全缓解期患者(n=31)外周血中CD4+T细胞、CD8+T细胞、TCRγδ+T细胞、CD4+CD25+调节性T细胞(Treg)、CD16+CD56+NK细胞比例;通过细胞杀伤实验分析NK细胞和γδT细胞的杀伤活性以及与Treg的关系。结果与对照组相比,初发白血病患者和完全缓解患者外周血中CD4+T细胞、CD8+T细胞比例无明显差异,但CD4+CD25+Treg比例明显增高,TCRγδ+T细胞和CD16+CD56+NK细胞比例明显下降。初发病患者NK细胞和γδT细胞具有杀伤活性,但Treg能明显抑制其杀伤活性。结论急性髓细胞白血病患者外周血γδT和NK细胞虽具有杀伤功能,但比例明显下降,Treg对其杀伤功能具有抑制作用。     

髓系来源抑制细胞的功能及其与自身免疫性疾病关系的研究进展

髓系来源抑制细胞(MDSC)是一群具有异质性的髓系细胞,在肿瘤、感染、创伤和自身免疫性疾病等病理状态下,会异常扩增并发挥免疫抑制作用。MDSC主要通过上调诱导型一氧化氮合酶(iNOS)和精氨酸酶(Arg)的表达,增加一氧化氮(NO)、活性氧(ROS)和过氧化硝酸盐(ONOO-)浓度,诱导调节性T细胞(Treg)分化等途径抑制获得性免疫;通过削弱自然杀伤(NK)细胞功能等途径抑制固有免疫。近年来MDSC在自身免疫性疾病中的作用日渐受到关注,参与了多发性硬化等多种自身免疫性疾病的免疫调控。现就MDSC及其与自身免疫性疾病关系的研究进展进行综述。     

髓系来源抑制细胞促进肿瘤免疫逃逸的研究进展

髓系来源抑制细胞(MDSC)是髓系来源的一群异质细胞,在荷瘤小鼠模型及肿瘤患者均发挥免疫抑制作用.肿瘤MDSC免疫逃逸作用的机制目前已取得了很多进展,这群细胞可以通过上调精氨酸酶1(ARN1),诱导一氧化氮合酶(iNOS or NOS-2)表达,增加一氧化氮(NO)、活化氧自由基(ROS)等的释放,分解肿瘤微环境中的半...     

舒尼替尼对转移性肾癌患者髓系来源抑制细胞的影响

舒尼替尼是一种口服的多靶点酪氨酸激酶抑制剂,具有抗血管生成和抑制肿瘤增殖的作用.与IFN-α相比,舒尼替尼明显提高了转移性肾癌(mRCC)患者的无进展生存期,并成为治疗mRGC的一线治疗方案.近期有研究报道,舒尼替尼还可以通过抑制髓系来源抑制细胞(MDSC)调节肿瘤免疫.MDSC是一群来源于髓系细胞谱系的异质细胞,其通...     

髓源性抑制细胞与肿瘤

髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是一类具有显著免疫抑制活性的异质细胞群,其通过抑制效应T细胞功能从而介导肿瘤免疫逃逸,促进肿瘤生长.该文就MDSCs在肿瘤免疫逃逸中的作用机制、肿瘤微环境中的各种细胞因子对MDSCs的影响及各种免疫活性细胞与MDSCs间的相互作用作一综述.     

间充质干细胞对髓源性抑制细胞免疫应答负性调控作用的影响

背景:髓源性抑制细胞是骨髓来源的一类异质性细胞群,能够抑制T细胞的功能,发挥免疫抑制作用。间充质干细胞是一种多能干细胞,可抑制先天性和适应性免疫反应。髓源性抑制细胞和间充质干细胞在免疫抑制功能上有许多相似之处,在肿瘤、炎症、移植等方面可产生相互联系。目的:综述基于髓源性抑制细胞的作用机制以及间充质干细胞对髓源性抑制细胞免疫应答负性调控作用的影响。方法:应用计算机检索Web of Science Core Collection数据库的相关文献,英文检索词为"Myeloid-derived suppressor cells""Mesenchymal stem cells""Stem cells",按纳入排除标准最终纳入49篇文献进行综述。结果与结论:髓源性抑制细胞通过分泌精氨酸酶1、诱导型一氧化氮合酶和吲哚胺2,3-双加氧酶等在体内发挥重要的免疫抑制功能。髓源性抑制细胞与间充质干细胞在自身免疫性疾病、器官移植、炎症感染、肿瘤等多种疾病治疗过程中通过不同机制相互作用,使肿瘤细胞逃避免疫监控,促进肿瘤进一步发展。在非肿瘤疾病中,髓源性抑制细胞发挥一定的良性调节作用,弱化机体自身的免疫反应,进而...     

髓系抑制性细胞与肿瘤免疫逃逸

近来研究发现在肿瘤患者体内聚积的一类髓系细胞与肿瘤免疫逃逸密切相关,通常称为髓系衍生抑制细胞。它在鼠中呈CD11b~+GR1~+,具有异质性和分化潜能。髓样抑制细胞的免疫抑制作用与精氨酸代谢密切相关。通过降低,这群细胞,或促使其分化,或抑制精氨酸代谢酶,可助于肿瘤免疫激活,将是很有前景的肿瘤免疫辅助治疗方法。     

小鼠肺肿瘤发展过程中外周血NKT和MDSC细胞变化

目的：探讨小鼠肺癌细胞生长过程中自然杀伤性T细胞（NKT）和骨髓源性抑制细胞（MDSC）变化。方法：采用小鼠Lewis肺癌细胞系（LLC）制备小鼠皮下肿瘤模型,在肿瘤生长不同时间取鼠尾血,提取白细胞进行相关抗体染色,采用流式细胞仪进行NKT和MDSC细胞检测。结果：肺癌小鼠随着肿瘤增大外周血NKT细胞比例逐渐降低,而MDSC细胞比例逐渐增加,与正常对照小鼠相比,二者均存在显著差异。结论：小鼠NKT细胞和MDSC细胞在肺肿瘤发展过程中呈相反趋势变化,二者可作为肺癌发展的潜在监测指标。     

IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function

Chronic inflammation is associated with promotion of malignancy and tumor progression. Many tumors enhance the accumulation of myeloid-derived suppressor cells (MDSC), which contribute to tumor progression and growth by suppressing anti-tumor immune responses. Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC possessing an enhanced capacity to suppress T cells. In this study, we found that the enhanced suppressive potential of IL-1β-induced MDSC was due to the activity of a novel subset of MDSC lacking Ly6C expression. This subset was present at low frequency in tumor-bearing mice in the absence of IL-1β-induced inflammation; however, under inflammatory conditions, Ly6C(neg) MDSC were predominant. Ly6C(neg) MDSC impaired NK cell development and functions in vitro and in vivo. These results identify a novel IL-1β-induced subset of MDSC with unique functional properties. Ly6C(neg) MDSC mediating NK cell suppression may thus represent useful targets for therapeutic interventions.     

髓样抑制细胞免疫抑制机理的研究

目的:研究荷瘤小鼠来源的髓样抑制细胞(Myeloid derived suppressor cell,MDSC)在肿瘤免疫抑制中的作用机理。方法:用Percoll分离法从荷瘤小鼠的脾脏和骨髓中分离Gr-1+CD11b+MDSC;用流式细胞术检测MDSC对T细胞增殖的抑制作用;分别用生化法和ELISA技术检测MDSC体外培养上清中抑制性因子NO、ROS和IL-10、TGF-β的含量。结果:MDSC在荷瘤小鼠的脾脏和骨髓中聚集增多,且其在骨髓中所占的比例显著高于脾脏;MDSC可以明显抑制脾脏细胞的增殖,体外培养6小时的MDSC可以分泌大量NO、ROS和IL-10、TGF-β。结论:本实验进一步证实MDSC可以通过分泌大量NO、ROS和IL-10、TGF-β抑制T细胞增殖。     

Metabolism of L-Arginine by Myeloid-Derived Suppressor Cells in Cancer: Mechanisms of T cell suppression and Therapeutic Perspectives

Patients with cancer have an impaired T cell response that can decrease the potential therapeutic benefit of cancer vaccines and other forms of immunotherapy. The establishment of a chronic inflammatory environment in patients with cancer plays a critical role in the induction of T cell dysfunction. The accumulation of myeloid-derived suppressor cells (MDSC) in tumor bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator of the induction of T cell suppression in cancer. Recent findings in tumor bearing mice and cancer patients indicate that the increased metabolism of L-Arginine (L-Arg) by MDSC producing Arginase I inhibits T cell lymphocyte responses. Here, we discuss some of the most recent concepts of how MDSC expressing Arginase I may regulate T cell function in cancer and suggest possible therapeutic interventions to overcome this inhibitory effect.     

肿瘤过继性细胞免疫治疗的研究进展

过继性免疫细胞能调节并增加肿瘤患者的免疫功能,有效克服肿瘤免疫逃逸机制。细胞因子诱导的杀伤细胞(CIK)、自然杀伤细胞(NK)、肿瘤浸润性淋巴细胞(TIL)、树突状细胞(DC)、T细胞受体修饰的T细胞(TCR-T)和嵌合抗原受体修饰的T细胞(CAR-T)分别以不同的机制直接杀伤或激发机体免疫反应杀伤肿瘤细胞,达到治疗肿瘤的目的。     

Human fibrocytic myeloid‐derived suppressor cells express IDO and promote tolerance via Treg‐cell expansion

By restraining T‐cell activation and promoting Treg‐cell expansion, myeloid‐derived suppressor cells (MDSCs) and tolerogenic DCs can control self‐reactive and antigraft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor‐free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC, which are differentiated from umbilical cord blood precursors by 4‐day culture with FDA‐approved cytokines (recombinant human‐GM‐CSF and recombinant human‐G‐CSF). This MDSC subset, characterized by the expression of MDSC‐, DC‐, and fibrocyte‐associated markers, promotes Treg‐cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes. In order to exert their protolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection.     

Arginase‐1 is neither constitutively expressed in nor required for myeloid‐derived suppressor cell‐mediated inhibition of T‐cell proliferation

Although previous reports suggest that tumor‐induced myeloid‐derived suppressor cells (MDSC) inhibit T cells by L‐arginine depletion through arginase‐1 activity, we herein show that arginase‐1 is neither inherently expressed in MDSC nor required for MDSC‐mediated inhibition. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor‐bearing mice were isolated and demonstrated potent inhibition in T‐cell proliferation activated by TCR‐ligation, Concanavalin A, PMA plus ionomycin, or IL‐2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase‐1 expression and/or exert their inhibitory effects independent of arginase‐1 activity. However, arginase‐1 expression in MDSC can be induced by exposure to TCR‐activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR‐activated T cells as orchestrating two signaling‐relay axes, IL‐6‐to‐IL‐4 and GM‐CSF/IL‐4‐to‐IL‐10, leading to arginase‐1 expression in MDSC. Specifically, IL‐6 signaling increases IL‐4R, enabling IL‐4 to induce arginase‐1 expression; similarly, GM‐CSF in concert with IL‐4 induces IL‐10R, allowing IL‐10‐mediated induction. Surprisingly, our study indicates that induction of arginase‐1 expression is not conducive to the critical MDSC‐mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD‐L1 blockade or SIRPα deficiency.     

Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner

Myeloid cells play a key role in the outcome of anti-tumor immunity and response to anti-cancer therapy, since in the tumor microenvironment they may exert both stimulatory and inhibitory pressures on the proliferative, angiogenic, metastatic, and immunomodulating potential of tumor cells. Therefore, understanding the mechanisms of myeloid regulatory cell differentiation is critical for developing strategies for the therapeutic reversal of myeloid derived suppressor cell (MDSC) accumulation in the tumor-bearing hosts. Here, using an in vitro model system, several potential mechanisms of the direct effect of paclitaxel on MDSC were tested, which might be responsible for the anti-tumor potential of low-dose paclitaxel therapy in mice. It was hypothesized that a decreased level of MDSC in vivo after paclitaxel administration might be due to (i) the blockage of MDSC generation, (ii) an induction of MDSC apoptosis, or (iii) the stimulation of MDSC differentiation. The results revealed that paclitaxel in ultra-low concentrations neither increased MDSC apoptosis nor blocked MDSC generation, but stimulated MDSC differentiation towards dendritic cells. This effect of paclitaxel was TLR4-independent since it was not diminished in cell cultures originated from TLR4-/- mice. These results support a new concept that certain chemotherapeutic agents in ultra-low non-cytotoxic doses may suppress tumor progression by targeting several cell populations in the tumor microenvironment, including MDSC.