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...     

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.     

Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of cytotoxic antitumor T effector cells. Heterogeneity in these cells poses a significant barrier to studying the in vivo contributions of individual MDSC subtypes. Herein, we show that granulocyte-macrophage colony stimulating factor, a cytokine critical for the numeric and functional development of MDSC populations, promotes expansion of a monocyte-derived MDSC population characterized by expression of CD11b and the chemokine receptor CCR2. Using a toxin-mediated ablation strategy to target CCR2-expressing cells, we show that these monocytic MDSCs regulate entry of activated CD8 T cells into the tumor site, thereby limiting the efficacy of immunotherapy. Our results argue that therapeutic targeting of monocytic MDSCs would enhance outcomes in immunotherapy.     

β‐glucan restores tumor‐educated dendritic cell maturation to enhance antitumor immune responses

Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid‐derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell‐based cancer vaccines can initiate antitumor immune responses, tumor‐educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β‐glucan on TEDCs and found that β‐glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with β‐glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T‐lymphocyte responses and led to a delay in tumor progression. These findings reveal that β‐glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β‐glucan in immunotherapy and suggesting its potential clinical benefit. β‐Glucan directly abrogated tumor‐educated dendritic cells‐associated immune suppression, promoted Th1 differentiation and cytotoxic T‐lymphocyte priming and improved antitumor responses.     

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。     

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.     

Targeting myeloid-derived suppressor cells for cancer therapy

The emergence and clinical application of immunotherapy is considered a promising breakthrough in cancer treatment. According to the literature, immune checkpoint blockade (ICB) has achieved positive clinical responses in different cancer types, although its clinical efficacy remains limited in some patients. The main obstacle to inducing effective antitumor immune responses with ICB is the development of an immunosuppressive tumor microenvironment. Myeloid-derived suppressor cells (MDSCs), as major immune cells that mediate tumor immunosuppression, are intimately involved in regulating the resistance of cancer patients to ICB therapy and to clinical cancer staging and prognosis. Therefore, a combined treatment strategy using MDSC inhibitors and ICB has been proposed and continually improved. This article discusses the immunosuppressive mechanism, clinical significance, and visualization methods of MDSCs. More importantly, it describes current research progress on compounds targeting MDSCs to enhance the antitumor efficacy of ICB.     

肿瘤微环境中免疫与炎症的调节

免疫和炎症构成肿瘤微环境的两大核心,但两者之间关系并不清楚。髓源抑制性细胞(myeloid derived suppressorcell,MDSC)和调节性T细胞(regulatory T cell,Treg)等抑制性细胞趋化至肿瘤部位可抑制炎症,而非介导肿瘤免疫逃逸;肥大细胞则通过对MDSC和Treg的调节,介导免疫和炎症的对话;作为肿瘤微环境中基本信号通路的Toll样信号可以直接调节免疫和炎症,并通过微颗粒途径精细调控肿瘤炎症的稳定。不管肿瘤炎症和免疫的关系如何复杂而交错,一般认为,肿瘤微环境的抗肿瘤免疫和炎症呈现出一种负相关关系,即在肿瘤的早期,免疫反应较强而炎症较弱;但在肿瘤的后期,免疫反应较弱而炎症较强。     

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.     

Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells

Tumor-induced T-cell tolerance is a major mechanism that facilitates tumor progression and limits the efficacy of immune therapeutic interventions. Regulatory T cells (Treg) play a central role in the induction of tolerance to tumor antigens, yet the precise mechanisms regulating its induction in vivo remain to be elucidated. Using the A20 B-cell lymphoma model, here we identify myeloid-derived suppressor cells (MDSC) as the tolerogenic antigen presenting cells capable of antigen uptake and presentation to tumor-specific Tregs. MDSC-mediated Treg induction requires arginase but is transforming growth factor-beta independent. In vitro and in vivo inhibition of MDSC function, respectively, with NOHA or sildenafil abrogates Treg proliferation and tumor-induced tolerance in antigen-specific T cells. These findings establish a role for MDSCs in antigen-specific tolerance induction through preferential antigen uptake mediating the recruitment and expansion of Tregs. Furthermore, therapeutic interventions, such as in vivo phosphodiesterase 5-inhibition, which effectively abrogate the immunosuppressive role of MDSCs and reduce Treg numbers, may play a critical role in delaying and/or reversing tolerance induction.     

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。     

Pattern response of dendritic cells in the tumor microenvironment and breast cancer

Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system’s status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells (DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenic phenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DC-based immunotherapy research has led to immense scientific advances, both in our understanding of the anti-tumor immune response and for the treatment of these patients.     

Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?

The tumor microenvironment consists of a variable combination of tumor cells, stromal fibroblasts, endothelial cells and infiltrating leukocytes, such as macrophages, T lymphocytes, and dendritic cells. A variety of cytokines, chemokines and growth factors are produced in the local tumor environment by different cells accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of multiple cell types. The interaction between cytokines, chemokines, growth factors and their receptors forms a comprehensive network at the tumor site, which is primary responsible for overall tumor progression and spreading or induction of antitumor immune responses and tumor rejection. Although the general thought is that dendritic cells are among the first cells migrating to the tumor site and recognizing tumor cells for the induction of specific antitumor immunity, the clinical relevance of dendritic cells at the site of the tumor remains a matter of debate regarding their role in the generation of successful antitumor immune responses in human cancers. While several lines of evidence suggest that intratumoral dendritic cells play an important role in antitumor immune responses, understanding the mechanisms of dendritic cell/tumor cell interaction and modulation of activity and function of different dendritic cell subtypes at the tumor site is incomplete. This review is limited to discussing the role of intratumoral cytokine network in the understanding immunobiology of tumor-associated dendritic cells, which seems to possess different regulatory functions at the tumor site.     

Melanoma-induced immunosuppression and its neutralization

Malignant melanoma is characterized by a rapid progression, metastasis to distant organs, and resistance to chemo- and radiotherapy. Well-defined immunogenic capacities of melanoma cells should allow a successful application of different immunotherapeutic strategies. However, the overall results of immunotherapeutic clinical studies are not satisfactory. These paradoxical observations are supposed to be due to the profound immunosuppression mediated by different mechanisms dealing with alterations in tumor and surrounding stroma cells. Melanoma microenvironment has been characterized by a remarkable accumulation of highly immunosuppressive regulatory leucocytes, in particular, myeloid-derived suppressor cells (MDSCs). Their migration, retention and high activity in the tumor lesions have been demonstrated to be induced by chronic inflammatory conditions developing in the tumor microenvironment and characterized by the long-term secretion of various inflammatory mediators (cytokines, chemokines, growth factors, reactive oxygen and nitrogen species, prostaglandins etc.) leading to further cancer progression. Here, we discuss the role of chronic inflammation in the recruitment and activation of MDSCs in melanoma lesions as well as therapeutic approaches of MDSC targeting to overcome tumor immunosuppressive microenvironment induced by chronic inflammation and enhance the efficiency of melanoma immunotherapies.     

Tumor-driven evolution of immunosuppressive networks during malignant progression

Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-beta, prostaglandin E(2), and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer.     

Cytotoxic T lymphocytes: role in immunosurveillance and in immunotherapy

Experiments in mice and recent human clinical studies have clearly shown the contribution of CD8+ T lymphocyte in the control of tumor development. CD8+ T lymphocytes are a constitutive component of the immune response during the development of cancer. In murine models, the efficiency of various cancer vaccines mainly depends on their ability to induce CD8+ T lymphocytes. Clinical responses in immunotherapy treated cancer patients have been associated with the presence of antitumor specific CD8+ T lymphocytes. In spontaneous regressive melanomas, intratumor antigen specific CD8+ cytotoxic T cells were expanded suggesting their involvement in the tumor shrinkage. Administration of antitumor specific cytotoxic T clones in mice resulted in antitumor responses which directly demonstrated the therapeutic efficiency of these cells. However, in most cases during cancer progression, the presence of antitumor CD8 T lymphocyte is not associated with clinical responses. Intrinsic functional abnormalities of these cells or a defect of CD8+ T cell migration to the tumor may in part explain their failure to inhibit tumor development. On the other hand, tumors also develop immune escape mechanisms (down modulation of tumor antigens, secretion of immunosuppressive factors, expression of anti-apoptotic molecules by the tumors, or pro-apoptotic factors inducing T cell death) to resist to the CD8+ T cell attack. To circumvent these tumor escape mechanisms, efficient cancer vaccines will have to recruit CD8+ T cells associated with other immune effectors.     

Tumor-Derived Transforming Growth Factor-β is Critical for Tumor Progression and Evasion from Immune Surveillance

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-β(TGF-β) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor  microenvironment. TGF-β produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-β in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-β using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ Treg cells, and consequently enhanced IFN-γ production by CTLs. Knockdown of tumor-derived TGF-β also significantly reduced the conversion of naïve CD4+ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-β suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-β is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-β may serve as a potential therapeutic approach for cancer.