What are regulatory T cells (Treg) regulating in cancer and why?

The role regulatory T cells (Treg) play in cancer development and progression is not clear. Earlier evidence suggested that CD4(+)FOXP3(+)CD25(high) Treg accumulate in tumors and the peripheral blood of patients with cancer and through suppression of anti-tumor immune responses promote tumor growth. However, more recent data indicate that in certain cancers, such as colorectal carcinoma (CRC), Treg suppress bacteria-driven inflammation which promotes carcinogenesis and thus benefit the host. Treg appear to play a dual role in cancer. This might explain why the frequency and functions of Treg are associated with a poor prognosis in some cancers but with favorable outcome in others. The clinical and prognostic significance of Treg in cancer depends on environmental factors, including infectious agents, tumor-derived products and locally-produced cytokines, which shape the nature of immune responses, including Treg generation, recruitment and survival. Adaptive or inducible (i) Treg or Tr1 are the major subset(s) of Treg present in cancer. These iTreg are a distinct subset of regulatory cells that phenotypically and functionally differ from FOXP3(+) natural (n) Treg responsible for peripheral tolerance. They mediate powerful suppression of effector T cells via diverse mechanisms, produce immunosuppressive cytokines, notably TGF-β as well as prostaglandin E2 and adenosine, and are resistant to apoptosis or oncological therapies. Strategies for silencing of Tr1 in patients with cancer will require novel approaches that can selectively deplete these cells or block molecular pathways they utilize.     

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

Toll-like receptor (TLR) agonists are potent activators of innate immune responses, activating dendritic cell (DC) maturation and inflammatory cytokine secretion by innate immune cells and as a consequence they promote adaptive immune response when coadministered with foreign antigens. There is also some evidence from mouse models that TLR ligands can help to break tolerance to self-antigens and promote immune responses to tumour antigens. Therefore, they have been exploited as adjuvants for tumour vaccines or as immunotherapeutics against cancer. Clinical evaluation of TLR agonists has resulted in a licensed immunotherapeutic for basal cell carcinoma, but there have also been disappointing results from clinical trials, with one pharmaceutical company recently halting its clinical programme. A major obstacle to the development of any active immunotherapeutic approach to cancer is the immunosuppressive environment of the growing tumour, including the induction of tolerogenic DCs and regulatory T (Treg) cells, which suppress the development of protective effector T-cell responses. This can be compounded by the use of TLR ligands as immunotherapeutics. A problem with TLR agonists that has not been fully appreciated is that they can generate suppressive as well as inflammatory responses in innate immune cells and can promote the induction of regulatory as well as effector T cells. This is part of a normal mechanism for limiting collateral damage during infection or sterile inflammation, but can constrain their ability to induce protective antitumour immunity, especially in the immune suppressed environment of the tumour. Alternatively, manipulating the TLR-activated innate immune responses to selectively blocking immunosuppressive arm, as well as that induced by the tumour, may hold the key to enhancing their efficacy as tumour immunotherapeutics and as adjuvants for cancer vaccines.     

Treg细胞与肿瘤免疫

免疫系统能准确地识别“自己”与“非已”，使机体产生保护性免疫应答，实现对肿瘤的监视。自Sakaguchi等。“首先报导CD4＋CD25＋T（Treg）细胞以来，关于Treg细胞的研究已成为免疫学界的热门课题之一。Treg细胞是具有免疫调节作用的T细胞亚群，其中Treg细胞与肿瘤免疫的研究更受学者们关注，本文就Treg细胞与肿瘤免疫机制的研究进展作简要回顾。     

Treg 细胞与乳腺癌的研究进展

CD4＋CD25＋调节性T细胞是一类具有特殊免疫调节功能的T细胞亚群,在机体免疫稳态维持、肿瘤免疫以及移植耐受等方面发挥着重要的作用。最近,大量的研究发现CD4＋CD25＋调节性T细胞在乳腺癌患者外周血和组织中表达增加,与肿瘤的发生、发展密切相关。本文就CIM＋CD25＋调节性T细胞与乳腺癌的关系作一简要综述。     

Identification of ABCG2⁺ cells in nasopharyngeal carcinoma cells

Tumor stem cells are a small subset of tumor cells with the ability of self-renewal and differentiation and are regarded as a cause of tumor growth and recurrence. Previously we have shown that stem-like label-retaining cells (LRCs) can be detected in nasopharynx, tongue, esophagus and xenograft tumors formed by nasopharyngeal carcinoma (NPC) cell lines (5-8F, 6-10B and TMNE). The present study aimed to identify ABCG2? cells in 5-8F NPC cells and compare their tumorigenic potential with ABCG2? cells, expecting that we can obtain insight into the mechanism of the differential phenotypes of ABCG2? and ABCG2? cells. By using magnetic cell sorting (MACS) method, we isolated ABCG2? cells and ABCG2? cells from 5-8F cells. Among these two subpopulations and unsorted 5-8F cells, the rate of ABCG2? cells at G1 phase was highest, while the rate of ABCG2? cells at S phase was highest, indicating that ABCG2? cells were mostly quiescent. However, ABCG2? cells showed lower cloning efficiency and tumorigenicity than ABCG2? cells. We also used Affymetrix U133 plus 2.0 human whole genome expression chip to identify the gene expression profile of ABCG2? and ABCG2? cells and found that both subpopulations expressed some stem cell associated genes, e.g., PSCA, ABCG2 and ALPI were expressed in ABCG2? cells, and K19, integrin α6, integrin β4, CD44 and K14 were expressed in ABCG2? cells, suggesting there were stem cells in both ABCG2? and ABCG2? cells. Our data demonstrated that there exist ABCG2? cells in NPC cells, but ABCG2 alone is not sufficient for isolating cancer stem cells in 5-8F NPC cells.     

B非霍奇金淋巴瘤患者Thl7、Treg水平及Thl7／Treg失衡的研究

目的比较健康人和淋巴瘤患者外周血中Thl7与Treg的水平,以及良性反应性淋巴结和淋巴瘤患者的淋巴结中Thl7与Treg的水平,探讨淋巴瘤患若是否存在TM7／Treg比例失衡。方法收集50例淋巴瘤患者的外周血及淋巴结,50例健康人外周血及50例良性反应性淋巴结。采用流式细胞术检测CD4、CD25、Foxp3和IL—17的表达,分析淋巴瘤患者与正常人的Thl7、Treg的水平及Thl7／Treg是否存在区别。结果与健康人外周血相比,淋巴瘤患者外周帆Treg增高,差异具有统计学意义,Thl7l和Thl7／Treg比例变化无统计学意义。然而与良性淋巴结相比,淋巴瘤患酱淋巴结内Thl7细胞降低,Thl7／Treg比例降低,Treg细胞增高,差异均具有统计学意义。结论淋巴瘤患者外周血和淋巴结中Treg比例增高,淋巴瘤患者淋巴结中Thl7／Treg比例明显失衡,Thl7／Treg的失衡存淋巴瘤的发生发展中可能起着重要的作用,明确两者之间的关系和免疫调节机制,并加以合理利用,有望为淋巴瘤的免疫治疗开辟新的思路。     

Stem cells of ependymoma

Ependymomas are tumours that arise throughout the central nervous system. Little is known regarding the aberrant cellular and molecular processes that generate these tumours.[第一段]     

Treg细胞与肿瘤免疫关系的研究进展

许多研究表明肿瘤内存在调节性T(Treg)细胞,Treg细胞在肿瘤局部可诱导免疫耐受.对肿瘤患者Treg细胞功能的深入研究将为肿瘤免疫治疗提供新的途径.     

Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells

Pulmonary metastasis of breast cancer requires recruitment and expansion of T-regulatory cells (Treg) that promote escape from host protective immune cells. However, it remains unclear precisely how tumors recruit Tregs to support metastatic growth. Here we report the mechanistic involvement of a unique and previously undescribed subset of regulatory B cells. These cells, designated tumor-evoked Bregs (tBreg), phenotypically resemble activated but poorly proliferative mature B2 cells (CD19(+) CD25(High) CD69(High)) that express constitutively active Stat3 and B7-H1(High) CD81(High) CD86(High) CD62L(Low) IgM(Int). Our studies with the mouse 4T1 model of breast cancer indicate that the primary role of tBregs in lung metastases is to induce TGF-β-dependent conversion of FoxP3(+) Tregs from resting CD4(+) T cells. In the absence of tBregs, 4T1 tumors cannot metastasize into the lungs efficiently due to poor Treg conversion. Our findings have important clinical implications, as they suggest that tBregs must be controlled to interrupt the initiation of a key cancer-induced immunosuppressive event that is critical to support cancer metastasis.     

NF-κB localization in multiple myeloma plasma cells and mesenchymal cells

Several reports demonstrated that the activation of Nuclear Factor-kappa B NF-κB is essential for the pathogenesis of multiple myeloma (MM). We analyzed the nuclear localization of NF-κB in MM-cells derived from 60 different patients with MM at presentation and in relapse, as well as in three myeloma cell lines. Nuclear localization (the active form) of NF-κB was detected in only one MM-sample from a refractory patient and in two samples from relapsed patients, while all the other samples, including the MM-cell lines, almost exclusively express the cytoplasmic (inactive) form of NF-κB. In mesenchymal cells from MM-patients NF-κB was clearly present in the nucleus. In addition, the proteasome inhibitor Bortezomib, which is described to antagonize NF-κB activity, had a consistent antitumor activity against both chemoresistant and chemosensitive MM-cells, regardless the NF-κB localization, thus suggesting the existence of other molecular targets of proteasome inhibitors in MM.     

Pancreatic stellate cells radioprotect pancreatic cancer cells through β1-integrin signaling

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong desmoplastic reaction where the stromal compartment often accounts for more than half of the tumor volume. Pancreatic stellate cells (PSC) are a central mediator of desmoplasia. There is increasing evidence that desmoplasia is contributing to the poor therapeutic response of PDAC. We show that PSCs promote radioprotection and stimulate proliferation in pancreatic cancer cells (PCC) in direct coculture. Our in vivo studies show PSC-dependent radioprotection in response to a single dose and to fractionated radiation. Abrogating β1-integrin signaling abolishes the PSC-mediated radioprotection in PCCs. Furthermore, this effect is independent of PI3K (phosphoinositide 3-kinase) but dependent on FAK. Taken together, we show for the first time that PSCs promote radioprotection of PCCs in a β1-integrin-dependent manner.     

子宫内膜异位症Treg细胞上调的机制研究

目的 研究子宫内膜异位症Treg细胞上调的原因.方法 选41例子宫内膜异位症患者,其中16例术前经过GnRH-a治疗的为治疗组,另25例术前未经治疗的为未治疗组,同时选25例子宫肌瘤患者为对照组,通过采血、腹腔液取样,用化学发光、流式细胞和ELISA方法检查化验,观察治疗组、未治疗组和对照组的基础雌二醇水平、腹腔液Tr...     

Dendritic cells: indispensable?

Dendritic cells (DCs) control the initiation and differentiation of T cells. In the steady state, DCs mediate tolerance. To achieve immunization, the tolerogenic function of DCs must be switched off by inducing their maturation with appropriate "adjuvants." Dendritic cells form a system composed of distinct subsets that differ in their expression of endocytic and signaling receptors. These subsets have different capacities to differentiate and polarize T cells and to cross-present antigen to expand CD8+ T cells. Optimization of vaccines is possible by exploiting the unique biological properties of DCs.     

ATP诱导胸腺Treg细胞表型改变的研究

目的： 研究外源ATP对Treg细胞特异性及其表型的影响。方法：制备胸腺单细胞悬液,分别加入0、0.01、 0.1、0.5和1 mmol/L浓度的外源性ATP,作用24 h后利用荧光检测法分析胞外ATP浓度,然后利用流式细胞仪分析作用72 h后胸腺细胞中Treg细胞比例的变化及其FOXP3和CD39表达的变化。结果：ATP作用72 h后,与对照组比较,胸腺细胞数减少,Treg细胞比例下调,以1 mmol/L作用组下调显著(t=5.260,P=0.034);Treg细胞中FOXP3和CD39的平均荧光强度(MFI) 上调,以较高浓度(0.5和1 mmol/L)ATP作用组上调显著(P均<0.05)。结论：较高浓度ATP会导致Treg细胞数减少,但存活Treg细胞特异性和功能相关表型因子表达增强。     

Neural stem cells, tumour stem cells and brain tumours： Dangerous relationships？

Institute of Cell and Molecular Science, Barts and the London, Queen Mary School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom. Neural stem cells （NSC） have been implicated not only in brain development and neurogenesis but also in tumourigenesis. Brain tumour stem cells （BTSC） have been isolated from several paediatric or adult human brain tumours,[第一段]     

肝细胞癌患者病灶局部Treg细胞分析及其临床意义

[目的]探讨肝细胞癌患者病灶局部Treg细胞的变化规律及其临床意义。[方法]收集40例原发性肝细胞型肝癌(HCC)患者经手术切除的肝癌组织及非癌肝组织(距肿瘤边缘>5cm)标本,用流式细胞仪分别检测肝癌组织、非癌肝组织中调节性T淋巴细胞(Treg细胞)的数量及变化规律,并且分析Treg细胞表达数量与预后的关系。[结果]肝癌病灶局部有不同程度免疫细胞浸润,主要为T淋巴细胞,其中Treg淋巴细胞含量高于非肿瘤组织。Ⅲ、Ⅳ期患者Treg细胞含量(7.7%±4.03%)明显高于Ⅰ、Ⅱ期患者(3.7%±1.6%)(P=0.037)。高Treg细胞含量组(≥6%)患者的预后明显差于低Treg细胞含量组(<6%)(P=0.005)。[结论]肝癌组织中,对免疫起抑制作用的Treg细胞比例增加。Treg细胞含量高与预后差相关。     

中晚期宫颈鳞癌患者治疗前外周血Treg计数分析

背景与目的：中晚期宫颈鳞癌同期放化疗(concurrent chemoradiotherapy,CCRT)治疗前性价比高的疗效判断方法较有限,该研究拟通过检测治疗前外周血CD4⁺CD25⁺CD127^Low/-调节性T细胞(regulatory T cells,Tregs)亚群计数及血清鳞癌抗原(squamous cell carcinoma antigen,SCC-Ag)水平,评价两者预测临床疗效的可行性。方法：采集44例Ⅱ_B~Ⅳ_A期宫颈鳞癌患者行CCRT治疗前的外周血标本,分别利用流式细胞免疫表型分析和酶联免疫法检测外周血CD4⁺CD25⁺CD127^Low/- Treg计数及血清SCC-Ag水平。收集临床和病理资料,并统计检验2个指标对疗效的预测作用。结果：治疗前外周血CD4⁺CD25⁺CD127^Low/- Treg计数在临床有效组低于无效组［(8.78±2.80)% vs (10.95±2.56)%,P<0.05］,血清SCC-Ag在不同临床疗效组间差异无统计学意义,且这2个、指标之间未发现相关性(Spearman’rho=-0.093,P=0.540)。经受试者工作特征(receiver operating characteristic,ROC)曲线确定治疗前外周血CD4⁺CD25⁺CD127^Low/- Treg及血清SCC-Ag最佳界值分别为9.76%与9.50 ng/mL。单因素分析显示,治疗前外周血CD4⁺CD25⁺CD127^Low/- Treg计数(OR=1.901,95%CI：1.112~3.219,P=0.017)对CCRT疗效有预测作用,而血清SCC-Ag水平无预测作用(OR=0.998,95%CI：0.001~4.253,P=0.897)。多因素Logistic回归分析显示,治疗前外周血CD4⁺CD25⁺CD127^Low/- Treg为独立的临床疗效预测因子(OR=3.115,95%CI：1.253~7.742,P=0.014)。结论：治疗前外周血CD4⁺CD25⁺CD127^Low/- Treg计数用于中晚期宫颈鳞癌患者CCRT临床疗效预测具有可行性。     

Perforin-mediated lysis of tumor cells by Mycobacterium bovis Bacillus Calmette-Guérin-activated killer cells.

Immunotherapy with Bacillus Calmette-Guérin (BCG) is clinically established in the treatment of superficial bladder cancer. In our attempt to clarify the underlying immunological mechanism, we could previously show that stimulation of PBMC with BCG leads to the generation of cytotoxic BCG-activated killer (BAK) cells. Among others, these BAK cells as well as lymphokine-activated killer (LAK) cells have been suggested as possible effector cells during BCG therapy. To understand BCG-induced activation of effector lymphocytes more precisely, we investigated the lytic pathways of human BAK cells and compared BAK cell cytotoxicity with LAK cell cytotoxicity. Perforin and Fas ligand (FasL) are the major cytolytic molecules of cytotoxic lymphocytes. Our results demonstrate that BAK and LAK cells showed an increased expression of perforin and FasL as compared with unstimulated controls. Killing of T-24 bladder tumor as well as Jurkat cells by BAK and LAK cells was predominantly mediated via perforin as demonstrated by a drastically reduced lysis in the presence of concanamycin A and EGTA/MgCl2, respectively. In contrast, lysis (radioactive release assay) and membrane disintegration (Annexin V binding) of both targets by BAK and LAK cells could not be blocked with an inhibitory anti-FasL monoclonal antibody (NOK-1). Nevertheless, T-24 and Jurkat were susceptible to killing by recombinant soluble FasL and by Chinese hamster ovary cells expressing membrane-bound FasL. We conclude that cellular mediators of BCG effector mechanisms, such as BAK and LAK cells, kill their targets via perforin and independent of the FasL pathway. Because we also found increased numbers of perforin-expressing lymphocytes in patients after BCG therapy, our findings have potential clinical relevance because BCG therapy would not be impaired by FasL resistance of target cells, which recently has been described for some tumors.     

Sarcoma arising from Langerhans cellsĭ

A rare case of tumor arising from Langerhans cells in the tongue and neck area in a 37 year-old man is presented. It was a polymorphocellular sarcoma with bean-like twisted nuclei. Electron microscopy identified granules of Langerhans (Bierbeck), multiple tubulo-vesicular structures, ring-like plates, Golgi apparatus, lysosomes and dendritic processes. Total leukocytic antigen was assayed in tumor cells but no expression of S-100 protein found.