Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer

It is well established that cancers affect differentiation of dendritic cells and promote systemic expansion of immune suppressive immature myeloid cells. This phenomenon may represent a mechanism of tumor escape from immune attack and could have significant impact on tumor progression. In this review we discuss the role of different tumor-derived factors, which were implicated in abnormal myeloid cell differentiation. The role of reactive oxygen species as well as JAK/STAT signaling in mechanisms of the effects of tumor-derived factors on myeloid cells is also discussed.     

Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses

Apoptotic cells can be eliminated by phagocytosis, which is mediated by antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs), through phosphatidylserine (PS) on apoptotic cells and phosphatidylserine receptor (PSR) on APCs. The phagocytosis of apoptotic cells by macrophages is strictly regulated by not only the inflammatory reaction, but also by an increase in anti-inflammatory factors such as IL-10, TGF-beta, and prostaglandin E2 (PGE2), leading to an anti-inflammatory situation, whereby apoptosis contributes to a noninflammatory response. However, because PS and PSR are expressed in cancer cells, shed soluble phosphatidylserine (sPS) can interact with the PS receptor on macrophages, which promotes an anti-inflammatory response to macrophages that may lead to immune escape. The sPS derived from cancer cells also reacts with the PSR on the cancer cells to produce IL-10, TGF-beta, and PGE2, which can cause suppression of anti-tumor immunity through the anti-inflammatory response to macrophages, which produces tumor-associated macrophages. Furthermore, sPS and TGF-beta inhibit the maturation of immature DCs, resulting in a functional inhibition of DCs. The potential roles of PS and PSR in cancer cells and macrophages in immune escape mediated by sPS and anti-inflammatory factors are discussed, which may explain their dual regulation of anti- and pro-inflammatory responses during tumor progression.     

鼻咽癌与免疫逃逸

肿瘤的免疫逃逸是癌症的一大特征,目前所知的肿瘤逃逸机制主要包括肿瘤的直接免疫逃逸和肿瘤微环境介导的免疫逃逸.鼻咽癌的发生发展与其肿瘤细胞的免疫逃逸密切相关,其中与鼻咽癌相关的肿瘤的直接免疫逃逸主要包括肿瘤细胞表面主要组织相容性复合体-Ⅰ类分子表达下降或缺失、肿瘤细胞缺乏共刺激分子以及Fas/FasL系统介导的免疫逃逸;与鼻咽癌相关的肿瘤微环境介导的免疫逃逸则包括肿瘤相关免疫抑制分子和肿瘤相关免疫抑制性细胞.研究鼻咽癌免疫逃逸的作用机制能够为其治疗及预防提供新的研究方向.     

肿瘤相关免疫抑制细胞与免疫逃逸誊几制研究进展

肿瘤相关树突细胞，髓系来源抑制细胞和肿瘤相关巨噬细胞等在肿瘤免疫逃逸过程中能够诱导免疫抑制反应。肿瘤源性因子可以影响其分化、功能和迁移。细胞内信号转导途径的激活可以调节细胞内代谢、细胞因子的产生和共刺激及共抑制分子的表达，由此产生免疫抑制作用。这些方面的研究将会为抗肿瘤免疫治疗提供新的策略。     

Heat shock protein 27 differentiates tolerogenic macrophages that may support human breast cancer progression

Tumor cells release several factors that can help the progression of the tumor by directly supporting tumor growth and/or suppressing host antitumor immunity. Here, we report that human primary breast tumor cells not only express elevated levels of heat shock protein 27 (Hsp27) at the intracellular level but also release extremely high levels of Hsp27 compared with the same patients' serum Hsp27 levels, predicting an acutely increased concentration of soluble Hsp27 in the human breast tumor microenvironment (HBTM). We demonstrate that Hsp27 levels in the HBTM can be extremely elevated as evidenced by high soluble Hsp27 levels in patients' tumor interstitial fluid. Because increasing numbers of tumor-associated macrophages (TAM) in the HBTM negatively correlate to patients' clinical outcomes and we have previously reported the immunoregulatory activity of soluble Hsp27, here, we tested for any specific effects of soluble Hsp27 on human monocyte to macrophage differentiation. We demonstrate that soluble Hsp27 causes the differentiation of monocytes to macrophages with immuno-tolerizing phenotypes (HLA-DRlow, CD86low, PD-L1high, ILT2high, and ILT4high). We detected the presence of TAMs with similar phenotypes in breast cancer patients. Hsp27-differentiated macrophages induce severe unresponsiveness/anergy in T cells. Moreover, these macrophages lose tumoricidal activity but become extremely proangiogenic, inducing significant neovascularization, a process that is critically important for tumor growth. Thus, our data demonstrate a novel immune escape and tumor growth-supporting mechanism mediated by soluble Hsp27 that may be operative in human breast cancer.     

Improving radioresponse through modification of the tumor immunological microenvironment

Radioresponse is influenced by factors apart from the targeted cancer cells; in fact, endothelial cells and infiltrating immune cells within the tumor microenvironment (TME) are the two main components affecting the outcome of radiotherapy. The benefits of fractionated radiotherapy are attenuated through the upregulation of hypoxia inducible factor-1 α and vascular endothelial growth factor. The therapeutic effect of antiangiogenic agents is counteracted by the mobilization of endogenous proangiogenic cells to the TME. This study highlights the importance of radiation timing within a vascular normalization window and discusses the importance of immune cells that comprise the microenvironment. A balance between favorable tumor-infiltrating immune cells, including cytotoxic T cells, natural killer cells, and dendritic cells, and the unfavorable cells, such as tumor-associated macrophages and regulatory T cells, determines the final tumor-control probability. The reciprocal complementation between combinations of radiotherapy and immunotherapy strategies through modulation of the tumor immunological microenvironment may yield promising results in the future.     

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.     

固有免疫细胞上Siglec在肿瘤中作用的研究进展与展望

免疫治疗给恶性肿瘤患者带来了新的希望。然而，常见的免疫治疗靶点，例如细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen-4，CTLA-4）、程序性死亡[蛋白]配体-1（programmed death ligand-1，PD-L1）在患者中阳性表达率低，只有少部分患者能从免疫治疗中获益，因此寻找新的免疫治疗靶点对于提高免疫治疗的响应率和效果极其重要。近期的研究提示唾液酸结合免疫球蛋白型凝集素（sialic acid-binding immunoglobulin-type lectin，Siglec）家族在巨噬细胞、自然杀伤（natural killer，NK）细胞和树突状细胞（dendritic cell，DC）等固有免疫细胞上表达丰富，并与肿瘤的发生、发展存在许多联系，有可能成为免疫治疗的下一个新靶点。在巨噬细胞上不同的Siglecs发挥不同的作用，Siglec-1增强巨噬细胞的抗原呈递作用，从而增强CD8⁺T细胞的杀伤作用；Siglec-7和Siglec-9诱导肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）向免疫抑制性TAM分化从而影响免疫微环境；Siglec-10与CD24相互作用保护肿瘤细胞免受巨噬细胞的攻击，Siglec-15也表现出类似PD-L1的相关作用，这些研究提示其有可能是全新的免疫检查点。NK细胞上高表达Siglec-7和Siglec-9，通过消除NK细胞表面的顺式相互作用，这些Siglec展现出免疫抑制作用。肿瘤表面高表达的唾液酸糖蛋白与NK细胞表面的Siglec相结合从而抑制NK细胞的杀伤作用，通过消除肿瘤表面的唾液酸可以增强NK细胞的杀伤力。有方案设想通过构建高亲合顺式配体来增强NK细胞杀伤力，但发现顺式配体的浓度会对NK细胞的杀伤力造成截然不同的影响，提示唾液酸存在某种动态平衡从而影响免疫反应。DC表面的Siglec-3和Siglec-9会与肿瘤黏蛋白相结合，诱导DC凋亡和减少免疫相关分子的产生进而造成免疫逃逸。在小鼠实验中证实相关Siglec影响DC的抗原呈递和免疫相关因子的表达。本综述总结了近期在固有免疫系统中，Siglec与肿瘤之间的相互作用以及Siglec影响肿瘤发生、发展的相关研究进展，讨论该家族成员作为免疫治疗新靶点的可能。     

肿瘤相关髓系细胞在多发性骨髓瘤中的研究进展

多发性骨髓瘤（MM）是一种血液系统恶性肿瘤,目前针对MM的治疗方案层出不穷,但仍不可治愈。除耐药外,MM不能治愈的另一个重要原因是肿瘤细胞与骨髓免疫微环境之间的相互作用所产生的免疫抑制,导致机体不能清除残留的肿瘤细胞。肿瘤相关髓系细胞（TAMC）是MM免疫抑制微环境的重要组成部分,在MM的免疫逃逸中发挥着极其重要的作用,同时也是限制免疫治疗效果提高的重要原因,成为了治疗MM的潜在靶点。文章系统阐述TAMC的组成及其在MM免疫微环境中作用机制的最新研究进展。     

Progressive growth of a murine T cell lymphoma alters population kinetics and cell viability of macrophages in a tumor-bearing host

Tumor progression induces infiltration of immune cell populations at the site of tumor growth. Infiltrated leukocyte population including monocyte and macrophages interacts with tumor cells and tumor microenvironment and results in the suppression of macrophage functions. Impaired functions of macrophages result in the suppression/inhibition of cell-mediated immunity leading to inefficient antitumor immune responses. Impaired macrophage population invariably helps in immune selection of tumor leading to uninterrupted growth and progression in the host. Murine T cell lymphoma designated as Dalton’s lymphoma is highly immunosuppressive and invasive tumor of T cell origin, which completely paralyzes the host’s immune system resulting in a very short life span of the host. Progressive growth of Dalton’s lymphoma (DL) cells has been known to inhibit the release of inflammatory cytokines and effector mediator molecules. In this study, we demonstrate that intraperitoneal transplant of DL cells in normal healthy host induces a rapid increase in macrophage cell population during early stage of tumor progression and progressive decrease in tumor-associated macrophage population and reduced survival of macrophages in advance stage of tumor burden.     

Human renal-cell carcinoma tissue contains dendritic cells

Immune surveillance of cancer requires antigen-presenting cells which activate T cells specific for tumor-associated antigens. We show here that substantial numbers of dendritic cells, which are the most potent antigen-presenting cells, emigrate from renal-tumor explants in organ culture. Tumor-derived dendritic cells presented with all characteristics of mature dendritic cells. Dendritic cells could be identified by typical cytoplasmic projections (=veils). They expressed high levels of MHC products and of the co-stimulator CD86 (B7-2). Dendritic cells expressed the CD45RO isoform but not CD45RA. The most important point was that up to 9% of the emigrating leukocytes expressed the CD83 antigen, a specific marker for mature dendritic cells. CD83⁺ cells were approximately 40-fold enriched in the tumor tissue as compared to the peripheral blood. In contrast to cultured blood dendritic cells, tumor-emigrant dendritic cells had a reduced potential to capture soluble antigen, as shown by the exclusion of fluoresceinated Dextran molecules. Finally, in mixed leukocyte reactions, tumor-derived dendritic cells were able to stimulate naive T cells from cord blood, which is a unique feature of dendritic cells. This study demonstrates that genuine dendritic cells reside in or infiltrate renal-cell carcinoma tissue. The failure of patients with renal-cell carcinoma to mount an anti-tumor immune response despite the presence of professional antigen-presenting cells in the tumor tissue suggests that tumor-associated dendritic cells are suppressed in situ, in a similar way to that described for tumor-infiltrating lymphocytes. © 1996 Wiley-Liss, Inc.     

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.     

外泌体在肿瘤细胞与TAMs之间相互作用中“桥梁”和调控作用的研究进展北大核心

外泌体是一类直径为30~100 nm的圆盘囊泡,其内包含许多组分,诸如复杂RNA和蛋白质等,主要参与细胞间的信号转导。肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)是肿瘤微环境中普遍存在的巨噬细胞,通过对肿瘤生长、免疫逃逸、侵袭和转移、耐药性等多方面的作用影响肿瘤进程。外泌体在肿瘤相关巨噬细胞的招募、极化及抗肿瘤免疫调控等方面发挥着重要的调节功能。同时,TAMs以外泌体为媒介作用于肿瘤细胞,从而构成了外泌体、TAMs与肿瘤细胞之间相互作用的调控通路。综上所述,本文旨在阐明肿瘤细胞与TAMs之间,以外泌体为“桥梁”相互影响的潜在机制,以及靶向肿瘤细胞和TAMs来源的外泌体在恶性肿瘤治疗中的展望。     

Fas/FasL与肿瘤局部及全身性免疫抑制

Ｆａｓ（ＣＤ９５）及其配体（ＦａｓＬ）属ＴＮＦ和ＮＧＦ受体家族,Ｆａｓ在多种质细胞表面均有表达。Ｆａｓ与ＦａｓＬ结合可引起多种细胞产生凋亡。近年来研究发现ＦａｓＬ在多种种瘤细胞的表面和细胞质中表达,同时已证实肿瘤周围激活的淋巴细胞表面有Ｆａｓ的表达,而这些淋巴细胞的凋亡异常增加,因此推测表达ＦｓａＬ的肿瘤细胞能诱发淋巴细胞的异常凋亡或抑制其功能,肿瘤细胞表面表达的ＦａｓＬ可能在局部免疫抑制中起着重     

The tumor microenvironment and its role in promoting tumor growth

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.