人体肿瘤髓系来源抑制性细胞的研究进展

髓系来源抑制性细胞(MDSC)是一群来源于髓系的异质性未分化成熟的细胞;在感染、创伤、败血症,尤其是肿瘤等病理状态下,MDSC在血液、淋巴器官、脾脏及肿瘤等组织中大量聚集;MDSC可以通过多种机制抑制肿瘤免疫,MDSC在患者外周血的数量与肿瘤的分期、负荷、远处转移及患者的预后密切相关.然而关于MDSC的研究结果大部分来自小鼠实验,由于肿瘤患者MDSC的表型比较复杂,其研究进展相对缓慢.     

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.     

抗肿瘤药物对髓系来源抑制性细胞的影响

髓系来源抑制性细胞(MDSC)在肿瘤发生发展过程中发挥重要的免疫抑制作用,许多肿瘤进展均伴有MDSC的异常聚集,许多因素均可影响MDSC的聚集和功能,在肿瘤治疗过程中如何有效降低MDSC的免疫抑制作用成为学者们关注的焦点.近来研究表明,抗肿瘤药物可以影响MDSC的许多生物学行为.     

膀胱癌患者外周血髓系来源的抑制细胞的比例及其临床意义

目的分析髓系来源的抑制细胞（myeloid-derived suppressor cells,MDSC）在膀胱癌患者外周血中的分布,初步探讨其临床意义。方法采用流式细胞术检测62例膀胱癌患者及20例健康人外周血中MDSC的比例,分析MDSC比例与临床病理特征和CD4＋CD25high调节性T细胞（Treg）的关系。结果与正常对照（0.122±0.043）%相比,膀胱癌患者外周血中MDSC比例明显增加（0.679±0.438）%,二者差异有显著性（P〈0.01）;手术后,患者外周血中MDSC的比例明显下降,与术前比较有统计学意义（P〈0.05）;MDSC水平与膀胱癌肿瘤分期明显相关,而与肿瘤的分化程度和患者外周血Treg水平无显著相关（P〉0.05）。结论膀胱癌患者外周血MDSC细胞水平明显升高,可能与肿瘤免疫功能低下及肿瘤发生发展密切相关。     

髓源性抑制细胞介导的免疫抑制

肿瘤患者体内积聚的一类髓系细胞与肿瘤免疫逃逸密切相关,称为髓源性抑制细胞( MDSC).在肿瘤患者体内血液、淋巴结以及骨髓中也存在着一群MDSC,对固有免疫系统和适应性免疫系统有抑制作用,髓样抑制细胞通过多条途径发挥免疫抑制作用.通过减少患者体内MDSC的数量或抑制MDSC相关的免疫抑制作用通路,在肿瘤治疗中将是很有前...     

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。     

髓源性抑制细胞和调节性T细胞在感染和肿瘤微环境中的免疫抑制机制

髓源性抑制细胞(MDSC)和调节性T细胞(Treg)是重要的抑制性免疫细胞,在炎症、感染和肿瘤中大量扩增,可通过多种机制抑制机体抗肿瘤免疫,促进肿瘤生长和转移.寻找肿瘤微环境中MDSC、Treg细胞升高的原因及清除方法,已成为肿瘤免疫治疗的研究热点.     

髓样来源抑制性细胞的研究进展

髓样来源的抑制性细胞(myeloid-derived suppressor cells,MDSC)是一群具有免疫抑制功能细胞的统称,通常认为它们是正常单核/巨噬细胞、DC细胞、粒细胞等处于分化的未成熟阶段,且可以分为单个核和分叶核两类。肿瘤模型小鼠中,单个核类MDSC典型的标记性分子是CD11b和Ly-6C,而分叶核类MDSC的典型标记分子是CD11b和Ly-6G;在肿瘤患者中,MDSC同时表达CD11和CD33等分子而不表达人白细胞抗原DR。MDSC由肿瘤微环境诱导产生,肿瘤产生过程中其在淋巴器官、血液以及病变部位聚集;针对不同的免疫细胞群,其通过分泌抑制性因子、接触性抑制以及诱导产生其他抑制性细胞等各种方式发挥免疫抑制作用,进而抑制天然免疫和适应性免疫。目前发现,MDSC抑制功能可以通过抗原特异性和抗原非特异性两种方式发挥作用,这是由其所处的局部微环境以及诱发其产生的肿瘤的性质来决定的。目前研究比较多的是其对NK细胞和T细胞的抑制作用,认为其主要可以通过产生精氨酸酶-1(arginase-1)、活性氧族(reactive oxygen species,ROS)以及抑制性的表面分子来实现对免疫系统的抑制作用,在肿瘤的生长以及转移过程中发挥重要的作用。     

水飞蓟素通过调控骨髓来源的抑制性细胞抗肺癌机制的实验研究

目的:研究水飞蓟素通过调控骨髓来源的抑制性细胞（MDSC）的抗肺癌机制。方法:我们在C57/BL6小鼠上构建了路易斯（Lewis）肺癌细胞转移瘤模型，灌胃给予不同浓度(25、50 mg/kg,每天一次)的水飞蓟素。测量小鼠肿瘤体积及体重变化。用免疫组化方法检测Lewis肺癌细胞肿瘤增殖相关指标增殖细胞核抗原（PCNA）的表达。通过TUNEL染色检测肺癌细胞的凋亡情况。通过免疫组化检测组织中CD8+ T细胞浸润及功能。通过流式细胞术检测CD11b+Gr-1+的MDSC百分比。通过Q-PCR检测肿瘤组织中Arg-1、iNOS2及MMP9的表达。结果:25和50 mg/kg的水飞蓟素剂量依赖地抑制肿瘤生长，诱导肿瘤细胞凋亡。水飞蓟素增加了CD8+ T细胞浸润；减少了肿瘤组织中MDSC的比例，肿瘤组织中Arg-1、iNOS2 及MMP9（MDSC功能相关） mRNA表达的减少也证实了MDSC功能的减弱。结论:水飞蓟素抑制了MDSC，促进CD8+ T细胞浸润及功能，抑制模型中肿瘤生长，为水飞蓟素治疗肺癌提供了依据。     

靶向髓系抑制性细胞抗肿瘤治疗策略研究进展

 髓系抑制性细胞（MDSC）来源于骨髓祖细胞和未成熟的髓细胞（IMC）,在荷瘤小鼠及肿瘤患者的骨髓、脾脏、外周血大量扩增,并募集到肿瘤组织。MDSC高表达精氨酸酶1（ARG1）、一氧化氮合酶（iNOS）、活性氧族（ROS）、过氧亚硝酸盐等介质,通过细胞接触依赖或非依赖方式诱导效应T细胞失能,或诱导调节性T细胞（Treg）等机制,抑制机体的抗肿瘤免疫功能。因此,靶向MDSC抗肿瘤策略成为研究热点,也取得了一定进展,现就当前靶向MDSC抗肿瘤免疫治疗策略及相关机制的研究进展做一简要介绍,为从事该领域的研究者提供参考。     

Resveratrol ameliorates Lewis lung carcinoma‐bearing mice development,decreases granulocytic myeloid‐derived suppressor cell accumulation and impairs its suppressive ability

Myeloid‐derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells which consist of 2 subsets: granulocytic MDSC (G‐MDSC) and monocytic MDSC (M‐MDSC). MDSC expand in tumor‐bearing hosts and contribute to immunotherapeutic resistance by remarkably blocking effector T‐cell activation via different mechanisms. Resveratrol (RSV) is a polyphenol and it has been widely used for its various health benefits. However, the underlying mechanism of its anti‐tumor properties remains unclear. In this study, a transplantable mouse model was used to investigate the effects of RSV on MDSC. The results showed that RSV ameliorated tumor development by decreasing G‐MDSC accumulation, impairing its suppressive ability on CD8⁺T cells and promoting M‐MDSC differentiation into CD11c⁺ and F4/80⁺ cells. Our results indicated that RSV should be considered as a modular of MDSC suppressive function and that RSV is a novel booster for tumor immunotherapy.     

Subpopulations of myeloid‐derived suppressor cells impair T cell responses through independent nitric oxide‐related pathways

The accumulation of myeloid‐derived suppressor cells (MDSC) in tumor‐bearing hosts is a hallmark of malignancy‐associated inflammation and a major mediator for the induction of T cell suppression in cancer. MDSC can be divided phenotypically into granulocytic (G‐MDSC) and monocytic (Mo‐MDSC) subgroups. Several mechanisms mediate the induction of T cell anergy by MDSC; however, the specific role of these pathways in the inhibitory activity of MDSC subpopulations remains unclear. Therefore, we aimed to determine the effector mechanisms by which subsets of tumor‐infiltrating MDSC block T cell function. We found that G‐MDSC had a higher ability to impair proliferation and expression of effector molecules in activated T cells, as compared to Mo‐MDSC. Interestingly, both MDSC subgroups inhibited T cells through nitric oxide (NO)‐related pathways, but expressed different effector inhibitory mechanisms. Specifically, G‐MDSC impaired T cells through the production of peroxynitrites (PNT), while Mo‐MDSC suppressed by the release of NO. The production of PNT in G‐MDSC depended on the expression of gp91^phox and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo‐MDSC. Deletion of eNOS and gp91^phox or scavenging of PNT blocked the suppressive function of G‐MDSC and induced anti‐tumoral effects, without altering Mo‐MDSC inhibitory activity. Furthermore, NO‐scavenging or iNOS knockdown prevented Mo‐MDSC function, but did not affect PNT production or suppression by G‐MDSC. These results suggest that MDSC subpopulations utilize independent effector mechanisms to regulate T cell function. Inhibition of these pathways is expected to specifically block MDSC subsets and overcome immune suppression in cancer.     

Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC survival was observed in the presence of MM-conditioned medium. Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival. In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.     

Invariant NKT cells are resistant to circulating CD15+ myeloid‐derived suppressor cells in patients with head and neck cancer

Myeloid‐derived suppressor cells (MDSC) are a heterogeneous population of immature and progenitor myeloid cells with an immunosuppressive role in various types of cancer, including head and neck squamous cell carcinoma (HNSCC). However, the effect on the host immune system, especially on invariant NKT (iNKT) cells with potent anti‐tumor activity, remains unclear. In this study, we investigated the effects of circulating MDSC subsets on the peripheral lymphocytes of patients with head and neck tumors. A significant accumulation of CD15⁺ granulocytic MDSC (G‐MDSC) and CD14⁺ monocytic MDSC (M‐MDSC) was demonstrated in HNSCC patients. The percentage of G‐MDSC showed an inverse correlation with the percentage of T cells in the peripheral blood. The increased G‐MDSC was significantly associated with advanced clinical stage and poor prognosis of HNSCC patients. The proliferation and viability of T cells were suppressed by CD15⁺ cells, and the suppression was reversed by adding the hydrogen peroxide scavenger catalase. However, iNKT cell activation upon α‐galactosylceramide (αGalCer) stimulation was not affected by the presence or absence of CD15⁺ G‐MDSC. These results indicate that increased G‐MDSC negatively affects peripheral T cell immunity, but not iNKT cells, in HNSCC patients, and that T cells are more sensitive to hydrogen peroxide produced by G‐MDSC than iNKT cells. Cancer immunotherapy designed to enhance the antitumor activity of iNKT cells by stimulation with αGalCer may remain effective in the presence of G‐MDSC.     

Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression

The tumor microenvironment is a complex milieu of tumor and host cells. Host cells can include tumor-reactive T cells capable of killing tumor cells. However, more frequently the tumor and host components interact to generate a highly immune suppressive environment that frustrates T cell cytotoxicity and promotes tumor progression through a variety of immune and non-immune mechanisms. Myeloid-derived suppressor cells (MDSC) are a major host component contributing to the immune suppressive environment. In addition to their inherent immune suppressive function, MDSC amplify the immune suppressive activity of macrophages and dendritic cells via cross-talk. This article will review the cell-cell interactions used by MDSC to inhibit anti-tumor immunity and promote progression, and the role of inflammation in promoting cross-talk between MDSC and other cells in the tumor microenvironment.     

Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) play an important role in tumor escape by suppressing T-cell responses. MDSC represent a group of cells of myeloid lineage at different stages of differentiation. Increased arginase activity and production of reactive oxygen species (ROS) are among the main functional characteristics of these cells. Recent studies have shown that all-trans retinoic acid (ATRA) had a potent activity in eliminating MDSC in cancer patients and in tumor-bearing mice. ATRA differentiates these cells into mature myeloid cells. However, the mechanism of this effect is unclear. Here, we have shown that ATRA dramatically and specifically up-regulated gene expression and protein level of glutathione synthase (GSS) in MDSC. This resulted in accumulation of glutathione (GSH) in these cells, observed in both mice and cancer patients. Blockade of GSH synthesis cancelled the effect of ATRA on MDSC. Accumulation of GSH in these cells using N-acetyl-L-cysteine mimicked the effect of ATRA on MDSC differentiation. Analysis of potential mechanisms of ATRA effect on GSS revealed that ATRA regulates its expression not by directly binding to the promoter but primarily via activation of extracellular signal-regulated kinase 1/2. Thus, ATRA induced differentiation of MDSC primarily via neutralization of high ROS production in these cells. This novel mechanism involves specific up-regulation of GSS and accumulation of GSH and could be used in developing and monitoring therapeutic application of ATRA.     

Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression

Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1beta promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonist-deficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which down-regulate tumor immunity is one of the mechanisms linking inflammation and cancer.     

髓源性抑制细胞在骨髓增生异常综合征中的研究进展

骨髓增生异常综合征(MDS)以造血细胞发育异常和无效造血为特征,骨髓造血微环境内髓源性抑制细胞(MDSC)的异常扩增和激活可能是重要原因。MDSC细胞扩增与激活导致自然杀伤细胞、CD8+T细胞功能低下与耗竭,并募集炎症细胞及因子,导致MDS患者遗传异常的进一步积累,致使MDS疾病进展。肿瘤环境炎症因子的积累诱导程序性死亡受体1(PD-1)在造血干、祖细胞上的表达和MDSC细胞程序性死亡受体配体1(PD-L1)过表达,PD-1/PD-L1的相互作用导致MDS造血祖细胞的凋亡和无效造血。靶向MDSC的试验及临床研究证实,纠正或逆转MDS免疫失调的骨髓微环境是恢复有效造血功能的治疗策略。     

Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in tumor-bearing subjects and which strongly inhibit anti-cancer immune responses. To study the biology of MDSC in colorectal cancer (CRC), we cultured bone marrow cells in conditioned medium from CT26 cells, which are genetically modified to secrete high levels of granulocyte-macrophage colony-stimulating factor. This resulted in the generation of high numbers of CD11b⁺ Ly6G⁺ granulocytic and CD11b⁺ Ly6C⁺ monocytic MDSC, which closely resemble those found within the tumor but not the spleen of CT26 tumor-bearing mice. Such MDSC potently inhibited T-cell responses in vitro, a process that could be reversed upon blocking of arginase-1 or inducible nitric oxide synthase (iNOS). We confirmed that inhibition of arginase-1 or iNOS in vivo resulted in the stimulation of cytotoxic T-cell responses. A delay in tumor growth was observed upon functional repression of both enzymes. These data confirm the role of MDSC as inhibitors of T-cell-mediated immune responses in CRC. Moreover, MDSC differentiated in vitro from bone marrow cells using conditioned medium of GM-CSF-secreting CT26 cells, represent a valuable platform to study/identify drugs that counteract MDSC activities.