综述:髓系衍生的抑制性细胞与肿瘤免疫耐受关系的研究进展

髓系衍生的抑制性细胞(myeloid-derived suppressor cells,MDSCs),是在肿瘤等病理因素的作用下髓系细胞发生分化障碍所产生的不同阶段髓系祖细胞的集合,具有广谱而强大的免疫抑制功能,是免疫系统的重要负性调节组件之一.研究表明:肿瘤微环境中的多种细胞因子或生长因子可通过激活相应的信号通路促进MDSCs扩增及活化,MDSCs进而通过多种机制抑制包括T细胞在内的多种免疫细胞的功能而促进肿瘤个体免疫耐受的发生.临床研究表明:肿瘤患者体内MDSCs的水平与肿瘤临床病程进展密切相关,基于MDSCs的免疫治疗也有望成为肿瘤免疫治疗的新策略.本文主要介绍了肿瘤中MDSCs的表型鉴定、扩增及活化机制、发挥免疫抑制作用的途径及机制、肿瘤中MDSCs的临床意义以及本领域需要解决的问题,以期对MDSCs在肿瘤免疫耐受中的作用进展提供参考.     

髓源性抑制细胞在肿瘤免疫中的作用

近来研究发现,一类被称为髓源性抑制细胞(Myeloid-derived suppressor cells,MDSCs)的细胞群,参与了肿瘤的免疫逃逸、免疫耐受、免疫抑制等病理过程,促进肿瘤的发生和生长。这群细胞主要分布在血液、脾、淋巴结、骨髓及肿瘤微环境等部位,通过复杂的分子途径,对机体的抗肿瘤免疫起抑制作用。本文就MDSCs在这方面作用的研究进展作一综述。     

髓系衍生的抑制性细胞与肿瘤免疫耐受关系的研究进展

髓系衍生的抑制性细胞(myeloid-derived suppressor cells,MDSCs),是在肿瘤等病理因素的作用下髓系细胞发生分化障碍所产生的不同阶段髓系祖细胞的集合,具有广谱而强大的免疫抑制功能,是免疫系统的重要负性调节组件之一.研究表明:肿瘤微环境中的多种细胞因子或生长因子可通过激活相应的信号通路促进MDSCs扩增及活化,MDSCs进而通过多种机制抑制包括T细胞在内的多种免疫细胞的功能而促进肿瘤个体免疫耐受的发生.临床研究表明:肿瘤患者体内MDSCs的水平与肿瘤临床病程进展密切相关,基于MDSCs的免疫治疗也有望成为肿瘤免疫治疗的新策略.本文主要介绍了肿瘤中MDSCs的表型鉴定、扩增及活化机制、发挥免疫抑制作用的途径及机制、肿瘤中MDSCs的临床意义以及本领域需要解决的问题,以期对MDSCs在肿瘤免疫耐受中的作用进展提供参考.     

MDSCs在恶性肿瘤中的生物学作用及其研究进展

髓源抑制性细胞(myeloid-derived suppressor cells,MDSCs)是一群以骨髓祖细胞和未分化成熟的粒细胞、树突状细胞、巨噬细胞为代表的异质髓细胞,表达的抗原标志多样且不同于成熟髓细胞。当机体处于癌症、炎症、感染等状态时,MDSCs首先从骨髓被募集到外周并在外周被活化,一系列肿瘤来源的慢性炎症相关的因子是介导MDSCs的募集和活化的关键。MDSCs有多种方法抑制机体的获得性和天然抗肿瘤免疫,来帮助肿瘤细胞逃避机体的免疫监视和攻击,促进肿瘤发展。近年来,越来越多的研究者开始关注MDSCs与恶性肿瘤的相关性而且靶向MDSCs的肿瘤免疫治疗也见于报道。本文旨在对MDSCs在恶性肿瘤中的生物学作用及研究进展作一简要综述。     

VEGF-A调节肿瘤中CD8^+ T细胞上抑制性分子的表达北大核心CSCD

在肿瘤的发生发展过程中,一个关键的步骤是肿瘤细胞产生免疫逃避机制,如诱导调节性 T 细胞（Treg）或髓源性抑制细胞（myeloid-derived suppressor cells,MDSCs）的分化,以及促进 T 细胞衰竭。T 细胞衰竭的主要特点是诱导 T 细胞表达免疫抑制性受体,如 PD-1、CTLA-4和 Tim3等,从而导致 T 细胞的效应功能受损。最近诸多研究发现阻断 PD-1或 CTLA-4等信号通路能够增强抗肿瘤免疫反应,从而抑制肿瘤的发生发展。但是肿瘤诱导 T 细胞表达 PD-1等抑制性分子的机制还不甚清楚。     

VEGF-A 调节肿瘤中 CD8＋T 细胞上抑制性分子的表达

在肿瘤的发生发展过程中,一个关键的步骤是肿瘤细胞产生免疫逃避机制,如诱导调节性T细胞(Treg)或髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)的分化,以及促进T细胞衰竭。T细胞衰竭的主要特点是诱导T细胞表达免疫抑制性受体,如PD-1、CTLA-4和Tim3等,从而导致T细胞的效应功能受损。最近诸多研究发现阻断PD-1或CTLA-4等信号通路能够增强抗肿瘤免疫反应,从而抑制肿瘤的发生发展。但是肿瘤诱导T细胞表达PD-1等抑制性分子的机制还不甚清楚。     

肿瘤发生过程中髓源性抑制细胞能量代谢的特点

髓源性抑制细胞(myeloid-derived suppressor cells, MDSCs)作为免疫调节细胞,在肿瘤发生和发展中起重要作用。糖代谢参与MDSCs功能的调节,但是,对于肿瘤进程中MDSCs代谢水平的变化,相关报道甚少。基于此,本研究利用小鼠肿瘤模型,采用流式细胞术先后分析肿瘤发生中MDSCs的丰度、周期及线粒体质量,利用ELISA试剂盒检测MDSCs乙酰辅酶A的含量,并在2-脱氧-D-葡萄糖(2-deoxy-D-glucose, 2-DG)改变糖代谢水平之后检测线粒体质量和细胞凋亡。结果发现:肿瘤发生中MDSCs的丰度明显增加,进入分裂期的细胞数增多;肿瘤状态下MDSCs乙酰辅酶A的含量增加,线粒体质量显著增加; 2-DG处理后,肿瘤条件下MDSCs的线粒体质量恢复至正常水平且细胞凋亡减少。以上结果表明,在肿瘤发生过程中, MDSCs主要依赖氧化磷酸化代谢获取能量,改变其糖代谢水平可能导致细胞功能变化。     

食药用真菌多糖对肿瘤免疫逃逸调节作用机制研究进展

食药用真菌多糖是食药用真菌的主要天然生物活性成分,可以从多层次、多靶点调节机体的免疫功能,被认为是一种天然免疫调节剂。此前食药用真菌多糖抗肿瘤机制研究集中在提升机体的免疫力达到抑制肿瘤的目的,但近年的研究表明它可以调节肿瘤微环境,恢复机体对肿瘤以及肿瘤微环境的监视能力,提升机体对肿瘤微环境的特异性免疫应答能力,进而达到充分发挥其抑制和杀伤肿瘤的功能。我们课题组前期研究中也发现食药用菌多糖可以正向调节肿瘤小鼠外周血免疫细胞数量,促进免疫细胞浸润到肿瘤微环境中帮助机体识别及杀伤肿瘤细胞,改善肿瘤微环境免疫状态。本文在我们团队的研究工作的基础上,结合国内外文献总结食药用真菌多糖作为免疫调节剂在抑制肿瘤免疫逃逸中的生物活性,结合肿瘤微环境探讨其与肿瘤免疫的关系、作用机制和在肿瘤治疗中的作用,以期为食药用真菌多糖免疫治疗提供新思路。     

外泌体在肿瘤免疫逃逸和耐受中的作用

肿瘤细胞能够通过多种机制抵御免疫防御或药物的抗肿瘤作用.近年研究发现,外泌体能够直接介导癌症的进展和远端转移灶的形成.更为重要的是,在肿瘤免疫微环境中,肿瘤来源外泌体不仅能够抑制树突状细胞(DC)、巨噬细胞、T细胞、NK细胞等免疫细胞功能,还能促进骨髓来源的抑制性细胞(MDSC)、调节性T细胞(Treg)等的免疫抑制功能,进而降低抗肿瘤免疫应答过程,帮助肿瘤细胞逃避机体免疫细胞识别.本文将概述肿瘤外泌体及其携带的关键介质分子在介导肿瘤免疫逃逸和耐受过程中扮演的角色,并对这一研究领域的最新进展作一综述.     

A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells whose numbers dramatically increase in chronic and acute inflammatory diseases, including cancer, autoimmune disease, trauma, burns and sepsis. Studied originally in cancer, these cells are potently immunosuppressive, particularly in their ability to suppress antigen-specific CD8(+) and CD4(+) T-cell activation through multiple mechanisms, including depletion of extracellular arginine, nitrosylation of regulatory proteins, and secretion of interleukin 10, prostaglandins and other immunosuppressive mediators. However, additional properties of these cells, including increased reactive oxygen species and inflammatory cytokine production, as well as their universal expansion in nearly all inflammatory conditions, suggest that MDSCs may be more of a normal component of the inflammatory response ("emergency myelopoiesis") than simply a pathological response to a growing tumor. Recent evocative data even suggest that the expansion of MDSCs in acute inflammatory processes, such as burns and sepsis, plays a beneficial role in the host by increasing immune surveillance and innate immune responses. Although clinical efforts are currently underway to suppress MDSC numbers and function in cancer to improve antineoplastic responses, such approaches may not be desirable or beneficial in other clinical conditions in which immune surveillance and antimicrobial activities are required.     

Circulating myeloid-derived suppressor cells: An independent prognostic factor in patients with breast cancer

Evading immune destruction is a hallmark of cancer. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid immune cells, are thought to foster the establishment of an immunosuppressive tumor microenvironment, but it remains unclear how. This study aims to determine the levels of circulating MDSCs and their subpopulations and test their immunosuppressive functions in patients with breast cancer (BC). We analyzed the fractions of MDSCs in freshly isolated peripheral blood mononuclear cells of patients with BC and healthy donors using flow cytometry. Circulating MDSCs were further phenotyped using fluorescently labeled antihuman monoclonal antibodies. Coculture experiments revealed the effects of MDSCs on CD3⁺ T cell response. Moreover, we correlated circulating MDSC levels with clinicopathological features of patients with BC. We show that the fraction of HLA-DR ^– CD33 ⁺ MDSCs in peripheral blood is about 10-fold higher in patients with BC than in healthy control individuals. The levels of all MDSC subpopulations, including monocytic and granulocytic MDSCs, are significantly elevated. Coculture experiments of purified HLA-DR ^– CD33 ⁺ MDSCs and CD3 ⁺ T cells demonstrate that T cell proliferation is more effectively inhibited by BC patient-derived MDSCs than by healthy control MDSCs. Moreover, increased circulating MDSC levels robustly associate with advanced BC stage and positive lymph node status. By being more abundant and more effective T cell suppressors, BC patient-derived circulating MDSCs exert a dual immunosuppressive effect. Our findings pave the way to develop novel diagnostic and immunotherapeutic strategies, aimed at detecting and inhibiting MDSCs in patients with BC.     

MDSCs might be “Achilles heel” for eradicating CSCs

During tumor initiation and progression, the complicated role of immune cells in the tumor immune microenvironment remains a concern. Myeloid-derived suppressor cells (MDSCs) are a group of immune cells that originate from the bone marrow and have immunosuppressive potency in various diseases, including cancer. In recent years, the key role of cancer stemness has received increasing attention in cancer development and therapy. Several studies have demonstrated the important regulatory relationship between MDSCs and cancer stem cells (CSCs). However, there is still no clear understanding regarding the complex interacting regulation of tumor malignancy, and current research progress is limited. In this review, we summarize the complicated role of MDSCs in the modulation of cancer stemness, evaluate the mechanism of the relationship between CSCs and MDSCs, and discuss potential strategies for eradicating CSCs with respect to MDSCs.     

Analysis of the control mechanism of lung cancer of caspase recruitment domain-containing protein 9 and myeloid-derived suppressor cell in Lewis lung cancer mice model

The purpose of this study was to explore the internal mechanism of lung cancer under the action of caspase recruitment domain-containing protein 9 (CARD9) and immunosuppressive cells myeloid-derived suppressor cells (MDSCs) in the Lewis lung cancer mice model. In this research, mice were selected as research objects, and the mechanism of CARD9 and immunosuppressive cells MDSCs in lung cancer was studied by experimental methods such as mRNA expression level, HE staining of tumor cells, and electron microscopy. The results showed that CARD9 regulated lung cancer by controlling the working state of immunosuppressive cells MDSCs and its downstream product indoleamine 2, 3-dioxygenase (IDO). The study confirmed the tumor regulatory mechanism of CARD9-MDSCs-NF-KB-IDO in MDSCs under tumor environment. In summary, the mechanism of CARD9 and immunosuppressive cells MDSCs in lung cancer was to achieve the goal of tumor control through the control of downstream product IDO. There are still some shortcomings in the research process, but the research results still provide some guidance for future research. Therefore, it is a research topic with practical significance.     

Myeloid-derived suppressor cells and tumor: Current knowledge and future perspectives

The immunosuppressive features of tumor lesions participate not only as one of the major players inducing cancer progression but also a big challenge for effective immunotherapy. It has been found that immunosuppression associated with chronic inflammatory factors, such as growth factors, cytokines, and chemokines is generated by stroma and tumor cells. Chronic and exhaustive secretion of these mediators triggers the generation of myeloid-derived suppressor cells (MDSCs) demonstrating one of the key players engaged in tumor immunosuppression. In point of fact, direct cell-to-cell contact is a prerequisite for immunosuppressive functions of MDSCs. From the clinical perspective, the frequency of peripheral blood MDSCs is correlated with clinical stage and therapeutic response in various cancers. Furthermore, MDSCs are involved in chemoresistant settings. Altogether, it is a rational therapeutic approach to block the fierce cycle in which MDSCs are developed and infiltrated to favor cancer progression. In this review, we will summarize recent findings of MDSCs in tumor progression and discuss potential therapeutic strategies that could be evaluated in future clinical trials.     

Signaling pathways involved in MDSC regulation

The immune system has evolved mechanisms to protect the host from the deleterious effects of inflammation. The generation of immune suppressive cells like myeloid derived suppressor cells (MDSCs) that can counteract T cell responses represents one such strategy. There is an accumulation of immature myeloid cells or MDSCs in bone marrow (BM) and lymphoid organs under pathological conditions such as cancer. MDSCs represent a population of heterogeneous myeloid cells comprising of macrophages, granulocytes and dendritic cells that are at early stages of development. Although, the precise signaling pathways and molecular mechanisms that lead to MDSC generation and expansion in cancer remains to be elucidated. It is widely believed that perturbation of signaling pathways involved during normal hematopoietic and myeloid development under pathological conditions such as tumorogenesis contributes to the development of suppressive myeloid cells. In this review we discuss the role played by key signaling pathways such as PI3K, Ras, Jak/Stat and TGFb during myeloid development and how their deregulation under pathological conditions can lead to the generation of suppressive myeloid cells or MDSCs. Targeting these pathways should help in elucidating mechanisms that lead to the expansion of MDSCs in cancer and point to methods for eliminating these cells from the tumor microenvironment.     

Polysaccharide from Lentinus edodes Inhibits the Immunosuppressive Function of Myeloid-Derived Suppressor Cells

Reversing the function of immune suppressor cells may improve the efficacy of cancer therapy. Here, we have isolated a novel polysaccharide MPSSS (577.2 Kd) from Lentinus edodes and examined its effects on differentiation and function of myeloid-derived suppressor cells (MDSCs). MPSSS is composed of glucose (75.0%), galactose (11.7%), mannose (7.8%), and xylose (0.4%). In vivo, it inhibits the growth of McgR32 tumor cells, which is correlated with a reduced percentage of MDSCs in peripheral blood. In vitro, it induces both morphological and biophysical changes in MDSCs. Importantly, MPSSS up-regulates MHC II and F4/80 expression on MDSCs, and reverses their inhibition effect on CD4⁺ T cells in a dose-dependent manner. The mechanism study shows that MPSSS may stimulate MDSCs through a MyD88 dependent NF-κB signaling pathway. Together, we demonstrated for the first time that MPSSS stimulates the differentiation of MDSCs and reverses its immunosuppressive functions, shedding new light on developing novel anti-cancer strategies by targeting MDSCs.     

Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity

Myeloid-derived suppressor cells (MDSCs) are primarily recognized for their immunosuppressive properties in malignant disease. However, their interaction with other innate immune cells and their regulation of immune responses, such as in parasitic infection, necessitate further characterization. We used our previously published mouse model of MDSC accumulation to examine the immunoregulatory role of MDSCs in B16 melanoma metastasis and Nippostrongylus brasiliensis infection. In this study, we demonstrate that the activity of MDSCs is dependent on the immune stimuli and subset induced. Monocytic MDSCs predictably suppressed antitumor immune responses but granulocytic MDSCs surprisingly enhanced the clearance of N. brasiliensis infection. Intriguingly, both results were dependent on MDSC interaction with mast cells (MCs), as demonstrated by adoptive-transfer studies in MC-deficient (Kit(Wsh)(/)(Wsh)) mice. These findings were further supported by ex vivo cocultures of MCs and MDSCs, indicating a synergistic increase in cytokine production. Thus, MCs can enhance both immunosuppressive and immunosupportive functions of MDSCs.