Absolute monocytosis at diagnosis correlates with survival in diffuse large B‐cell lymphoma—possible link with monocytic myeloid‐derived suppressor cells

Some patients with lymphoma have monocytosis at diagnosis, but its significance is unclear. The recently recognized subpopulation, monocytic myeloid‐derived suppressor cells (M‐MDSCs), has immunoregulatory function, suppresses host anti‐tumour immunity and plays a role in cancer tolerance. Data from 91 untreated patients with diffuse large B‐cell lymphoma (DLBCL) were evaluated for monocytosis >1000/mm³ at diagnosis and its significance compared with a number of well‐established prognostic factors for DLBCL including age, stage, gender, B symptoms, extranodal sites, LDH and CRP levels, bone marrow involvement and International Prognostic Index (IPI) score. In 23 of these patients with DLBCL and 15 healthy controls, the proportion of M‐MDSCs in the peripheral blood was determined by flow cytometry. Monocytosis was found in 17.6% of the patient cohort examined. In the multivariate analysis, bone marrow involvement, IPI score and monocytosis were the only independent prognostic factors seen to be associated with decreased progression free and overall survival. Patients with DLBCL had on average increased M‐MDSCs counts at diagnosis compared with controls, which returned to normal after achieving remission. In conclusion, monocytosis was identified as an independent prognostic factor in DLBCL and correlated with worse overall survival. The significant increases in the M‐MDSCs pool observed in some of the cases examined may possibly help to explain why monocytosis is associated with poor outcome in these patients. Copyright © 2012 John Wiley & Sons, Ltd.     

The influence of myeloid‐derived suppressor cells on angiogenesis and tumor growth after cancer surgery

While myeloid‐derived suppressor cells (MDSCs) have been reported to participate in the promotion of angiogenesis and tumor growth, little is known about their presence and function during perioperative period. Here, we demonstrated that human MDSCs expressing CD11b⁺, CD33⁺ and HLA‐DR^– significantly increased in lung cancer patients after thoracotomy. CD11b⁺ CD33⁺ HLA‐DR^– MDSCs isolated 24 hr after surgery from lung cancer patients were more efficient in promoting angiogenesis and tumor growth than MDSCs isolated before surgical operation in allograft tumor model. In addition, CD11b⁺ CD33⁺ HLA‐DR^– MDSCs produced high levels of MMP‐9. Using an experimental lung metastasis mouse model, we demonstrated that the numbers of metastases on lung surface and Gr‐1⁺ CD11b⁺ MDSCs at postoperative period were enhanced in proportion to the degree of surgical manipulation. We also examined that syngeneic bone marrow mesenchymal stem cells (BMSCs) significantly inhibited the induction and proliferation of Gr‐1⁺ CD11b⁺ MDSCs and further prevented lung metastasis formation in the mice undergoing laparotomy. Taken together, our results suggest that postoperatively induced MDSCs were qualified with potent proangiogenic and tumor‐promotive ability and this cell population should be considered as a target for preventing postoperative tumor metastasis.     

Induction of myeloid‐derived suppressor cells by tumor exosomes

Myeloid‐derived suppressor cells (MDSCs) promote tumor progression. The mechanisms of MDSC development during tumor growth remain unknown. Tumor exosomes (T‐exosomes) have been implicated to play a role in immune regulation, however the role of exosomes in the induction of MDSCs is unclear. Our previous work demonstrated that exosomes isolated from tumor cells are taken up by bone marrow myeloid cells. Here, we extend those findings showing that exosomes isolated from T‐exosomes switch the differentiation pathway of these myeloid cells to the MDSC pathway (CD11b⁺Gr‐1⁺). The resulting cells exhibit MDSC phenotypic and functional characteristics including promotion of tumor growth. Furthermore, we demonstrated that in vivo MDSC mediated promotion of tumor progression is dependent on T‐exosome prostaglandin E2 (PGE2) and TGF‐β molecules. T‐exosomes can induce the accumulation of MDSCs expressing Cox2, IL‐6, VEGF, and arginase‐1. Antibodies against exosomal PGE2 and TGF‐β block the activity of these exosomes on MDSC induction and therefore attenuate MDSC‐mediated tumor‐promoting ability. Exosomal PGE2 and TGF‐β are enriched in T‐exosomes when compared with exosomes isolated from the supernatants of cultured tumor cells (C‐exosomes). The tumor microenvironment has an effect on the potency of T‐exosome mediated induction of MDSCs by regulating the sorting and the amount of exosomal PGE2 and TGF‐β available. Together, these findings lend themselves to developing specific targetable therapeutic strategies to reduce or eliminate MDSC‐induced immunosuppression and hence enhance host antitumor immunotherapy efficacy. © 2008 Wiley‐Liss, Inc.     

Elevated chronic inflammatory factors and myeloid‐derived suppressor cells indicate poor prognosis in advanced melanoma patients

Chronic inflammation is considered to be one of the hallmarks for tumor initiation and progression. Moreover, a long‐term production and accumulation of inflammatory factors lead to a local and systemic immunosuppression associated with cancer progression. However, the correlation between inflammatory mediators, immunosuppressive cells and the clinical outcome of malignant melanoma patients was poorly investigated. In this study, we performed a complex analysis of various inflammatory factors, myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the peripheral blood of patients suffering from malignant melanoma of different stages. We demonstrated that levels of serum IL‐1β, IFN‐γ and CXCL10 were significantly increased in advanced melanoma patients. In addition, these factors were found to be associated with an increased frequency of MDSCs and Tregs as compared to age‐ and gender‐matched healthy donors. Importantly, advanced melanoma patients with signs of progression displayed markedly elevated concentrations of IL‐1β and CXCL10 as compared to patients with stable disease. Moreover, an enrichment of circulating monocytic (Mo)‐MDSCs significantly correlated with a decreased progression free survival of these patients. Our data highlight a complex association between circulating inflammatory mediators, Mo‐MDSCs and the clinical outcome as well as suggest that their levels in patients with advanced melanoma are of important prognostic value allowing the identification of those with high risk of disease progression.     

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid‐derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI⁺ SRT⁺) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy.     

Myeloid‐derived suppressor cells as effectors of immune suppression in cancer

The tumor microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid‐derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumor factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and the malignant cells. An increased presence of MDSCs is associated with tumor progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this article, we will review our current understanding of the mechanisms that underlie MDSC expansion and their immune‐suppressive function. Finally, we review the preclinical studies and clinical trials that have attempted to target MDSCs, in order to improve responses to cancer therapies.     

Enhanced suppressive capacity of tumor‐infiltrating myeloid‐derived suppressor cells compared with their peripheral counterparts

Although the main site of action for myeloid‐derived suppressor cells (MDSCs) is most likely the tumor microenvironment, so far the study of these cells has been largely restricted to spleen‐derived MDSCs. In this study, we compared the suppressive capacity of splenic and tumor‐derived MDSCs in different subcutaneous mouse tumor models. We investigated which suppressive mechanisms were involved. Finally, we investigated whether MDSCs and regulatory T cells (T_reg) cooperate in the suppression of T‐cell responses. In all models, splenic granulocytic MDSCs (grMDSC) strongly suppress CD4⁺ T‐cell proliferation while the suppressive effect on CD8⁺ T cells is less pronounced. Splenic monocytic MDSCs (moMDSC) have a lower suppressive capacity, compared to grMDSC, on both CD4⁺ and CD8⁺ T‐cell proliferation. Both grMDSC and moMDSC isolated from the tumor have a much stronger suppressive activity compared to MDSCs isolated from the spleen of tumor‐bearing mice, associated with a higher NO₂^? production by the tumor‐derived moMDSC and arginase activity for both subsets. The expression of CD80 is also elevated on tumor‐derived grMDSC compared with their peripheral counterparts. Direct contact with tumor cells is required for the upregulation of CD80 and CD80⁺ MDSCs are more suppressive than CD80^? MDSCs. Coculture of T_reg and MDSCs leads to a stronger suppression of CD8⁺ T‐cell proliferation compared to the suppression observed by T_reg or MDSCs alone. Thus, we showed that tumor‐infiltrating MDSCs possess a stronger suppressive capacity than their peripheral counterparts and that various suppressive mechanisms account for this difference.     

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.     

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.     

髓源抑制性细胞与恶性肿瘤的研究进展

髓源抑制性细胞(myeloid derived suppressor cells,MDSCs)是一群异质性细胞,包括多种处于不同分化阶段的髓样细胞,如髓系祖细胞、未成熟的巨噬细胞、粒细胞、单核细胞、树突状细胞等。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中存在大量MDSCs的扩增,与肿瘤的进展密切相关。恶性肿瘤来源的多种因子如粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony stimulating factor,GM-CSF）、白细胞介素（interleukin,IL）-6、S100钙结合蛋白A8/A9（S100 calcium binding protein A8/A9,S100A8/A9）等是导致MDSCs扩增的关键因素。MDSCs可通过抑制机体抗肿瘤免疫、上皮-间质转化(epithelial-mesenchymal transition,EMT）、侵袭、血管生成、转移前小生境形成等多种途径导致肿瘤发生发展。本文主要介绍MDSCs的亚群、功能、募集和活化机制,MDSCs作为预后标志物的价值以及当前靶向MDSCs的抗肿瘤治疗策略,以期加深对MDSCs与恶性肿瘤关系的认识。     

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。     

Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages

During carcinogenesis, tumors induce dysfunctional development of hematopoietic cells. Myeloid lineage cells, in the form of myeloid derived suppressor cells (MDSCs) and alternatively polarized M2 macrophages, influence almost all types of cancers by regulating diverse facets of immunosuppression, angiogenesis, cell proliferation, growth and metastasis. One-third of Americans are obese, and accumulating evidence suggests that obesity is a risk factor for various cancers. However, the relationship between these immune players and obesity are not well-described. In this review, we evaluate potential mechanisms through which different aspects of obesity, namely insulin resistance, increased estrogen, adiposity and low grade chronic inflammation from adipose tissue macrophages, may coalesce to promote MDSC induction and M2 macrophage polarization, thereby facilitating cancer development. Detailed understanding of the interplay between obesity and myeloid mediated immunosuppression may provide novel avenues for therapeutic targeting, with the goal to reduce the challenge obesity presents towards gains made in cancer outcomes.     

髓源性抑制细胞——肿瘤免疫治疗的新靶点

髓源性抑制细胞(Myeloid-derived suppressor cells,MDSCs)是在病理情况下扩增的一种髓源性抑制细胞群,其特点是能负向调节机体的抗肿瘤免疫反应从而促进肿瘤的发生和发展.通过阻断MDSCs的免疫抑制通路来提高肿瘤免疫治疗的效果,是一个颇有前景的治疗策略.     

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...     

MicroRNA‐155 deficiency enhances the recruitment and functions of myeloid‐derived suppressor cells in tumor microenvironment and promotes solid tumor growth

Immune cells in tumor microenvironment play a prominent role in tumor progression and metastasis. MicroRNA‐155 (miR‐155) represents an important player in innate and adaptive immunity by regulating differentiation, maturation and activation of macrophages, dendritic cells, B cells and T cells. However, the role of miR‐155 expression in immune cells in solid tumor development is less elucidated. Our current study showed that both B16‐F10 melanoma and Lewis lung carcinoma tumors grew much faster in bic/miR‐155 knockout (miR‐155^?/?) mice along with an increase of myeloid‐derived suppressor cells (MDSCs) accumulation in tumors, compared to that in wild‐type mice. Bone marrow transplantation study showed that bone marrow miR‐155 deficiency could replicate the above tumor‐promoting phenotype. In vitro study demonstrated that tumor‐infiltrating miR‐155^?/? MDSCs showed greater migration ability and expressed higher level of multiple chemokines. Furthermore, we found that the level of HIF‐1α, a direct target of miR‐155, was increased in miR‐155 deficient MDSCs, and that the increased HIF‐1α upregulated CXCL1, CXCL3 and CXCL8 expression in MDSCs, contributing to the enhanced recruitment of miR‐155^?/? MDSCs to the tumors. Moreover, miR‐155^?/? MDSCs showed enhanced immunosuppressive and pro‐angiogenic capacities. Taken together, our study, for the first time, demonstrated that miR‐155 deficiency promoted solid tumor growth through increasing the recruitment of MDSCs to tumor microenvironment and enhancing the tumor‐promoting functions of the recruited MDSCs. Thus, upregulating miR‐155 expression in MDSCs may be developed as a therapeutic approach to halt tumor development.     

NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma

Objective:Esophageal squamous cell carcinoma (ESCC) has high morbidity and mortality rates worldwide. Cancer stem cells (CSCs) may cause tumor initiation, metastasis, and recurrence and are also responsible for chemotherapy and radiotherapy failures. Myeloid-derived suppressor cells (MDSCs), in contrast, are known to be involved in mediating immunosuppression. Here, we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated. Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) was knocked down and overexpressed by lentiviral transfection. Quantitative PCR, Western blot, immunohistochemistry, cell invasion, flow cytometry, cell sorting, multiplex chemokine profiling, and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs. Only NEDD9 was upregulated in CSCs using the sphere-forming method. NEDD9 expression was correlated with tumor invasion (P = 0.0218), differentiation (P = 0.0153), and poor prognosis (P = 0.0373). Additionally, NEDD9 was required to maintain the stem-like phenotype. Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8 (CXCL8) expression via the ERK pathway. CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo. MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC, NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor, suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.     

Recruited monocytic myeloid‐derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL‐1β‐mediated increase in E‐selectin expression

The tumor premetastatic niche initiated by primary tumors is constructed by multiple molecular factors and cellular components and provides permissive condition that allows circulating tumor cells to successfully metastasize. Myeloid‐derived suppressor cells (MDSCs), a population of immature cells in pathological conditions, play a critical role in the formation of the premetastatic niche. However, few researches are focused on the function of monocytic MDSCs (mo‐MDSCs), a subtype of MDSCs, in the construction of the niche. Here, we show that the number of mo‐MDSCs is significantly increased in the premetastatic lungs of tumor‐bearing mice, thus promoting tumor cell arrest and metastasis. Before the arrival of tumor cells, the lung‐recruited mo‐MDSCs produced IL‐1β, thereby increasing E‐selectin expression and promoting tumor cell arrest on endothelial cells. Depletion of mo‐MDSCs in the premetastatic lungs decreased IL‐1β production, resulting in reduced E‐selectin expression. In addition, compared with alveolar macrophages and interstitial macrophages, mo‐MDSCs were the major source of IL‐1β expression in the premetastatic lungs. Cytokine array analyses and transwell experiments revealed that CCL12 recruits mo‐MDSCs to premetastatic lungs. CCL12 knockdown in tumor‐bearing mice significantly decreased mo‐MDSC infiltration into the premetastatic lungs, leading to reduced E‐selectin expression. Overall, the permissive conditions produced by the infiltrated mo‐MDSCs correlated with increased tumor cell arrest and metastasis. These results reveal a novel role of mo‐MDSCs in constructing the premetastatic niche. Thus, inhibition of mo‐MDSCs infiltration may change the premetastatic niche to normal condition and attenuate tumor metastasis.     

髓源抑制性细胞的功能及其逆转策略

髓源抑制性细胞（myeloid-derived suppressor cell,MDSC）是在骨髓中产生的一群具有高度异质性的免疫抑制细胞, 在 肿瘤等病理状态下大量聚集,是促进肿瘤进展、降低患者对传统治疗反应性的关键因素。近年来,免疫检查点阻断剂和基因工程 T细胞过继回输治疗延长了许多晚期恶性肿瘤患者的生存期,但上述免疫疗法在肺癌、结直肠癌等实体瘤中有效率仅为 15%~40%,这与实体瘤免疫抑制微环境密切相关。MDSC在肿瘤微环境中聚集,通过抑制T细胞或NK细胞增殖及功能减弱宿主 抗肿瘤免疫反应,是患者对免疫治疗耐受的关键机制。因此,明确MDSC聚集及功能特征是探索提高免疫治疗效果的重要研究 方向。本文将系统阐述MDSC的产生、聚集及其免疫抑制功能的调控机制,概述目前靶向MDSC治疗的最新研究进展。