髓系抑制性细胞在肝癌发病中的作用研究进展

髓系抑制性细胞（MDSCs）是备受关注的免疫抑制性细胞,具有调节免疫应答的作用。近年发现MDSCs与肝癌发生发展及预后密切相关,肝癌微环境中多种因子影响MDSCs的扩增、活化和募集,而MDSCs通过下调机体的抗肿瘤免疫应答或诱导免疫耐受形成,促进肿瘤的生长与转移。研究MDSCs在肝癌免疫逃逸的作用,将为肝癌早期发现、诊断及免疫治疗等提供新线索。     

常见恶性肿瘤中CAF来源外泌体的研究进展

癌相关成纤维细胞(CAF)是纤维细胞、骨髓间充质细胞和内皮细胞在一定细胞因子的作用下转化而成,分泌多种生物活性物质和吸引炎性细胞参与肿瘤微环境调控的肿瘤相关细胞.CAF分泌胶原蛋白、细胞因子和外泌体等调节细胞周围微环境,外泌体可以介导CAF向肿瘤细胞进行物质和信号传递,发挥调节肿瘤免疫抑制、改善肿瘤细胞生长微环境,提高...     

肿瘤微环境调节型细胞器靶向递药系统的研究进展

近年来,利用机体免疫系统进行抗肿瘤的免疫疗法受到了广泛关注。然而抑制性肿瘤微环境限制了免疫治疗的效果,因此克服肿瘤微环境及其中的免疫抑制性细胞的作用成为肿瘤免疫疗法的一大热点。纳米制剂具有重新编程免疫抑制性微环境的巨大潜力,为免疫治疗提供了有效策略。随着主动靶向性纳米载体技术的不断发展和对药物作用位点研究的不断深入,具有更精准主动靶向功能的亚细胞器靶向性纳米载体材料也受到越来越多的关注。本文简要介绍了各亚细胞器与肿瘤的关系,概述了基于酸碱性调节、活性氧含量、免疫原性及免疫抑制细胞的肿瘤微环境特点的纳米药物靶向递送系统的设计策略与研究进展,为亚细胞器途径靶向递药系统的构建及其在肿瘤免疫治疗方面的应用提供借鉴和参考。     

肿瘤免疫治疗新靶标PGE2受体EP4的研究进展

肿瘤免疫治疗已成为人们对抗癌症的重要手段,但响应率低仍是目前亟需解决的关键问题。大量研究表明,逆转肿瘤免疫抑制是阻断肿瘤免疫逃逸、增强和扩大免疫疗法疗效的重要策略。前列腺素E₂(PGE₂)是肿瘤微环境中的强效免疫介质,可特异性结合细胞膜上的七次跨膜蛋白EP4受体,诱导肿瘤微环境免疫抑制,驱动肿瘤免疫逃逸。特异性阻断PGE₂/EP4信号通路可有效解除肿瘤微环境免疫抑制,增强抗肿瘤免疫反应,促进肿瘤消退。本文从EP4受体的结构、信号转导、调控机制及其拮抗剂开发现状等方面阐述了EP4受体在肿瘤免疫治疗领域的新进展和新发现,并展望了新的发展方向。     

成纤维细胞激活蛋白α与肿瘤微环境的免疫抑制

成纤维细胞激活蛋白α(FAPα)是肿瘤微环境中特异性表达于肿瘤相关成纤维细胞(TAF)表面的抗原分子,属丝氨酸蛋白酶家族Ⅱ型膜整合糖蛋白,具有二肽酶和胶原酶活性,对肿瘤微环境的免疫抑制和肿瘤浸润转移有重要作用.因此,FAPα已被视为理想的肿瘤治疗靶标.本文综述了FAPα阳性细胞对肿瘤微环境免疫抑制状态的形成及靶向FAPα治疗的研究.     

MDSCs在脓毒症免疫抑制中的机制研究进展

髓源性抑制细胞（MDSCs）是一群异质性、具有免疫抑制功能的未成熟髓样细胞。常在肿瘤免疫逃避机制的研究中被提及,除此之外,MDSCs还参与慢性炎症、感染、自身免疫性疾病、创伤等疾病的免疫调节。最近研究发现,MDSCs在脓毒症的发病机制中也起着关键作用。脓毒症是由于宿主对感染的免疫反应失调而导致危及生命的器官功能衰竭。有研究表明,与脓毒症幸存者相比,非幸存者的淋巴细胞显著减少。在脓毒症发病早期,MDSCs被招募到炎症部位,起到抑制炎症的作用;然而,如果MDSCs数量增多及其组织浸润持续存在,可导致显著的病理生理学改变（如淋巴细胞减少、宿主免疫抑制和免疫瘫痪）,从而导致患者病情快速进展甚至愈后恶化。由此可见,MDSCs为脓毒症患者淋巴细胞减少提供了新的见解,现已成为脓毒症研究的一个新兴课题,并可能为脓毒症患者提供新的治疗靶点。本文综述了MDSCs的生物学特征及其在脓毒症免疫抑制中的作用机制,以期为脓毒症的基础研究和临床治疗提供新的靶点和思路。     

转化生长因子β在肿瘤微环境中的作用及其靶向药物研究进展

转化生长因子β (transforming growth factor-β, TGF-β)是一种多效性细胞因子, 属于调节细胞生长和分化的TGF-β超家族。在肿瘤发展的后期, 自分泌和旁分泌的TGF-β可能通过诱导上皮-间质转化、促进肿瘤血管生成、调节免疫抑制来调控肿瘤的转移和复发。因此, TGF-β被认为是晚期肿瘤生长、进展和转移潜能的重要因素。中和或阻断TGF-β是一种干预和干扰肿瘤生长关键启动子的独特方法, 可能会提供一个新的治疗机会。此文就TGF-β的结构、功能及其在肿瘤微环境中的作用机制进行综述, 并列举了一些在研的靶向TGF-β药物, 旨在为抗肿瘤药物的开发和临床应用提供参考。     

肿瘤相关巨噬细胞在卵巢癌微环境中的作用及研究进展

卵巢癌在女性生殖系统肿瘤发病率中排名第三,但死亡率却位居第一,独特的肿瘤微环境(TME)促使其易于转移和复发。肿瘤相关巨噬细胞(TAM)作为肿瘤微环境中的重要角色分为M1和M2表型,通过分泌细胞因子参与调控肿瘤发展、耐药、预后、转移等过程。本文综述肿瘤相关巨噬细胞在卵巢癌微环境中的作用及研究进展,为以卵巢癌相关巨噬细胞分泌的细胞因子为靶标的靶向治疗提供依据,以期开辟卵巢癌靶向治疗新方式。     

肿瘤微环境在皮肤癌发生发展中的作用及相关治疗研究进展

目前,皮肤癌发病率高居不下且仍缺乏有效的治疗方案。肿瘤微环境是肿瘤发生发展的局部环境,由肿瘤相关成纤维细胞、肿瘤相关脂肪细胞、免疫细胞、内皮细胞和神经元等细胞成分及细胞外基质等非细胞成分组成,具有低氧、酸性和免疫抑制等特点,影响皮肤癌进展,并对维持皮肤癌异质性和耐药性起重要作用。靶向肿瘤微环境是对抗耐药性和降低皮肤癌死亡率的有效途径。本综述主要介绍肿瘤微环境中细胞外基质、相关基质细胞及低氧和酸性环境对皮肤癌进展的影响,讨论靶向肿瘤微环境的途径和方法,为皮肤癌治疗提供新思路。     

乳酸在肿瘤微环境中的免疫调节作用

在氧气充足时,肿瘤细胞会增加葡萄糖的摄取并将大量丙酮转化为乳酸。这种有氧糖酵解现象被称为Warburg效应(Warburg effect)。而产物乳酸作为癌细胞改造微环境的重要工具,促进肿瘤侵袭与转移,并通过诱导和招募免疫抑制相关细胞和分子,有利于肿瘤发生发展。乳酸通过单羧酸转运蛋白从癌细胞流出并防止胞内酸化,可抑制T淋巴细胞和NK (natural killer)细胞的细胞毒活性,并促进树突细胞(dendritic cells, DCs)向分泌白介素10的耐受性DCs分化。此外,通过组蛋白赖氨酸残基的乳酸化修饰,乳酸可促进巨噬细胞向M2样表型极化,从而抑制肿瘤微环境内的免疫反应。本综述从乳酸代谢过程、乳酸对免疫细胞的影响等方面系统地阐释了乳酸作为免疫抑制分子的作用。此外,揭示了组蛋白乳酸化修饰在乳酸调节细胞代谢和功能中发挥的重要作用,并探索了靶向乳酸代谢过程中的潜在靶点用于癌症治疗的可能性,最终提出通过抑制糖酵解途径和乳酸生成与转运的相关蛋白的肿瘤免疫联合治疗策略。     

信号素 3F及其受体神经纤毛蛋白在肿瘤微环境中的研究进展

肿瘤微环境可以经不同信号通路分泌多种血管生成因子、炎性细胞因子和趋化因子,利用多种间质细胞组成的庞杂系统加快肿瘤的进展.其中信号素(semaphorins,SEMA)是肿瘤微环境的重要调节因子,信号素-神经纤毛蛋白(SEMA-NRP)复合物参与肿瘤抑制途径,本研究期望通过对肿瘤微环境中信号素3F(semaphorins 3F,SEMA3F)及其受体神经纤毛蛋白(neuro?pilin,NRP)作用的综述,为将来对肿瘤进行早期靶向治疗提供依据.     

Myeloid cell population dynamics in healthy and tumor-bearing mice

Tumor growth is often associated with the aberrant systemic accumulation of myeloid-derived suppressor cells (MDSCs), which are a heterogenous population of cells composed of polymorphonuclear neutrophils, monocytes, macrophages, dendritic cells and early myeloid precursors. These MDSCs are thought to suppress anti-tumor T cell responses in both tumor tissues and secondary lymphoid tissues. Accumulation of MDSCs in these target tissues is a dynamic process associated with medullary and extramedullary myelopoiesis and subsequent cellular migration. Here, we review the current understanding of the cellular, molecular, hematological and anatomical principles of MDSC development and migration in tumor-bearing mice. We also discuss the therapeutic potential of chemokines that influence the balance between MDSC subpopulations.     

Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice

Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a key role in the suppression of the innate and adaptive immunity. Chemotherapeutic strategies have been developed to deplete or deactivate MDSCs in different tumor models. The pyrimidine analog, 5-fluorouracil (5-FU) is found to reduce the tumor size by depleting MDSCs. Here, we asked whether the purine analog, fludarabine (Flu), could exert similar effects. Employing a lymphoma model, we demonstrated that in mice with advanced tumors (where MDSC-induced suppression was present), treatment with a single low-dose Flu (25, 50, 100 mg/kg) elevated the numbers of splenic MDSCs and serum arginase activity, and simultaneously, increased the tumor growth (only the highest dose). On the other hand, in mice with palpable tumors (where the MDSC-induced suppression was in progress), treatment with Flu had no significant effects on the tumor growth or the number of splenic MDSCs. In contrast to Flu, treatment with low-dose 5-FU, irrespective of tumor stage, caused tumor regression which coincided with significant reductions in the numbers of splenic MDSCs and blood neutrophils, but increases in the ratios of splenic CD4⁺ T and CD8⁺ T cells to suppressive MDSCs. Finally, in healthy mice (where MDSC-induced immuosuppression did not exist), 5-FU, but not Flu induced significant decreases in the number of myeloid cells in the bone marrow, naturally occurring splenic MDSCs and thymocytes. In conclusion, Flu exacerbates MDSC-induced immunosuppression in a tumor stage-dependent manner, whereas 5-FU alleviates the suppressive effects of MDSC at all stages of tumor development.     

Immunotherapeutic modulation of the suppressive liver and tumor microenvironments

The liver is an immunologically unique organ, consisting of resident hematopoietic and parenchymal cells which often contribute to a relatively tolerant microenvironment. It is also becoming increasingly clear that tumor-induced immunosuppression occurs via many of the same cellular mechanisms which contribute to the tolerogenic liver microenvironment. Myeloid cells, consisting of dendritic cells (DC), macrophages and myeloid derived suppressor cells (MDSC), have been implicated in providing a tolerogenic liver environment and immune dysfunction within the tumor microenvironment which can favor tumor progression. As we increase our understanding of the biological mechanisms involved for each phenotypic and/or functionally distinct leukocyte subset, immunotherapeutic strategies can be developed to overcome the inherent barriers to the development of improved strategies for the treatment of liver disease and tumors. In this review, we discuss the principal myeloid cell-based contributions to immunosuppression that are shared between the liver and tumor microenvironments. We further highlight immune-based strategies shown to modulate immunoregulatory cells within each microenvironment and enhance anti-tumor responses.     

Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation

Tumor microenvironment is a complex and highly dynamic milieu that provides very important clues on tumor development and progression mechanisms. Tumor-associated endothelial cells play a key role in stroma organization. They achieve tumor angiogenesis, a formation of tumor-associated (angiogenic) vessels mainly through sprouting from locally preexisting vessels and/or recruitment of bone marrow-derived endothelial progenitor cells. This process participates to supply nutritional support and oxygen to the growing tumor. Endothelial cells constitute the interface between circulating blood cells, tumor cells and the extracellular matrix, thereby controlling leukocyte recruitment, tumor cell behavior and metastasis formation. Hypoxia, a critical parameter of the tumor microenvironment, controls endothelial/tumor cell interactions and is the key to tumor angiogenesis development. Under hypoxic stress, tumor cells produce factors that promote angiogenesis, vasculogenesis, tumor cell motility, metastasis and cancer stem cell selection. Targeting tumor vessels is a therapeutic strategy that has lately been fast evolving from antiangiogenesis to vessel normalization as discussed in this review. We shall focus on the pivotal role of endothelial cells within the tumor microenvironment, the specific features and the part played by circulating endothelial precursors cells. Attention is stressed on their recruitment to the tumor site and their role in tumor angiogenesis where they are submitted to miRNAs-mediated de/regulation. Here the compensation of the tumor deregulated angiogenic miRNAs - angiomiRs - is emphasized as a potential therapeutic approach. The strategy is to over express anti-angiomiRs in the tumor angiogenesis site upon selective delivery by precursor endothelial cells as miRs carriers.     

Brain tumor-targeted drug delivery strategies

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.Key words: Barriers targeting, Tumor microenvironment, Tumor cells, Systematic targeted drug delivery     

外泌体微小RNA作为肺癌标志物的研究进展

肺癌是当今致死率较高的癌症之一,其早期诊断对于提高治疗效果至关重要.外泌体是肿瘤细胞信号传导过程中的一种重要方式,其内容物包括蛋白质、脂类物质、mRNAs、微小RNA(microRNAs)等.肿瘤细胞和微环境中其他细胞均可以向细胞外基质中释放外泌体,进而参与调控肿瘤的发生和发展.外泌体可体现其来源细胞的部分重要生物学特...     

MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy

Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), and stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased GM-CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting are being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells. GM-CSF's role in promoting MDSC survival in patient tumors is supported by the observation that GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.