Dendritic cells in tumor immunology and immunotherapy

Despite rapid advances in cancer therapeutics, relapsed disease due to failed immunosurveillance remains a major problem in many cancers. Dendritic cells are recognized as key to the induction of immune responses to cancer and intensive study is underway to facilitate their use in cancer immunotherapy. In initial clinical trials, dendritic cell preparations were, with the benefit of hindsight, largely sub-optimal, yet encouraging results have been seen. The challenge now is to expand our knowledge of the interactions between tumors and the immune system, through basic scientific research and coordinated large-scale clinical studies. This review focuses on the anti-tumor immune response, human dendritic cell biology and the results of recent clinical studies of dendritic cell immunotherapy for cancer.     

Dendritic cells: activation and maturation--applications for cancer immunotherapy

There is an increasing number of studies utilizing dendritic cell (DC) based therapies for cancer. With a powerful antigen-presentation capability, DCs have the potential to overcome tumor tolerance and induce anti-tumor immunity, when loaded with tumor antigens. In order to optimize this approach, methods have aimed to enhance immunopotency of therapeutic DCs. A thorough understanding of DC immunobiology would accelerate this process and provide advantageous procedures to increase anti-tumor responses. This review contains an analysis of recent advances on DC subsets, phenotypic characterization, localization, surface receptors and their ligands. The events of immune induction via DCs, involving initial recognition and uptake of antigens, migration, subsequent activation and maturation are revisited. Furthermore, the current methods used for DC-based cancer immunotherapy, including DCs pulsed with tumor antigens in forms of DNA, RNA, peptides, proteins and lysates, or DCs fused with tumor cells are summarized. Respective preclinical and clinical trials are in progress and hold promise for developing effective cancer vaccines.     

Dendritic cells: immunological features and utilisation for tumour immunotherapy

The prospect of developing 'magic bullets' to attack tumour cells has been a goal of biologists for decades. Abundant experimental and clinical observations demonstrating that an effective specific immune response may engender tumour regression has prompted efforts to find an immunotherapeutic approach to this problem. The most important arm of cellular immunity for such responses appears to be cytotoxic T-lymphocytes (CTL) which can recognise antigen on virtually all cell types and which are key to the elimination of virally-infected cells. The specific activation and maintenance of activity of these cells is therefore the major goal of designing a therapeutic cancer vaccine. Advances in our understanding of the role of dendritic cells (DC) in priming and modifying immune responses suggest that they should be potent adjuvants for vaccination. The use of antigens targeted to the major histocompatibility complex (MHC) molecules expressed on these cells as an approach to tumour immunotherapy has already been tested in the treatment of many malignancies, and recent findings shed light on additional directions through which their efficacy may be improved.     

Dendritic cell-based immunotherapy in thyroid malignancies

A new approach for anti-tumor immunotherapy is to use dendritic cells (DCs) as adjuvants in order to actively immunize cancer patients with antigens specifically expressed in tumor cells. DCs possess a unique capacity to effectively activate CD4+ T helper cells and CD8+ cytotoxic T cells. During the last years, several clinical trials in various malignancies demonstrated that immunizations with tumor antigen pulsed DCs could break the tolerance of the immune system against antigens expressed by the tumor cells resulting in partial or complete remission in some cases. This review describes the most important findings on the interaction between DCs and T cells as well as natural killer cells and summarizes recent data on DC vaccination of endocrine and non-endocrine malignancies. The results from current pilot studies suggest that DC vaccination may represent a promising strategy for the development of an anti-cancer vaccine to treat chemotherapy and radioresistant endocrine malignancies.     

Dendritic cell-based approaches to cancer immunotherapy

Immunologic approaches to the treatment of malignancies are currently enjoying a resurgence of enthusiasm due to the discovery of tumour-associated antigens and the requirements for stimulating a tumour antigen-specific immune response. The goal of the newer strategies is to stimulate immunity against specific tumour-associated antigens, rather than to broadly, but non-specifically, stimulate the immune system. Since dendritic cells, professional antigen-presenting cells, play a central role in stimulating immune responses in vivo, there is considerable interest in immunising patients with autologous dendritic cells loaded with tumour antigens of interest. Methods for generating large numbers of dendritic cells under clinically-applicable conditions have been developed and it has been shown that they may be loaded with antigen in many different forms including proteins or peptides, RNA or DNA and cellular extracts. Ongoing research is seeking to optimise the purity, antigen loading and maturation of the dendritic cells. Phase I clinical trials have been initiated in order to study the safety and feasibility of immunisations with dendritic cells in humans with various malignancies. Phase II studies will be performed to establish which tumours and clinical scenarios will be most relevant for dendritic cell immunotherapy. Although the commercial applicability of dendritic cell-based immunotherapy has been recognised by the biotechnology industry, commercial availability of dendritic cell vaccines await phase III studies.     

Dendritic cell-based approaches to cancer immunotherapy

Immunologic approaches to the treatment of malignancies are currently enjoying a resurgence of enthusiasm due to the discovery of tumour-associated antigens and the requirements for stimulating a tumour antigen-specific immune response. The goal of the newer strategies is to stimulate immunity against specific tumour-associated antigens, rather than to broadly, but non-specifically, stimulate the immune system. Since dendritic cells, professional antigen-presenting cells, play a central role in stimulating immune responses in vivo, there is considerable interest in immunising patients with autologous dendritic cells loaded with tumour antigens of interest. Methods for generating large numbers of dendritic cells under clinically-applicable conditions have been developed and it has been shown that they may be loaded with antigen in many different forms including proteins or peptides, RNA or DNA and cellular extracts. Ongoing research is seeking to optimise the purity, antigen loading and maturation of the dendritic cells. Phase I clinical trials have been initiated in order to study the safety and feasibility of immunisations with dendritic cells in humans with various malignancies. Phase II studies will be performed to establish which tumours and clinical scenarios will be most relevant for dendritic cell immunotherapy. Although the commercial applicability of dendritic cell-based immunotherapy has been recognised by the biotechnology industry, commercial availability of dendritic cell vaccines await phase III studies.     

Natural and induced regulatory T cells: targets for immunotherapy of autoimmune disease and allergy

Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the 'holy grail' for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells.     

Dendritic cells in pathogenesis of COPD

COPD (Chronic Obstructive Pulmonary Disease) is an important lung and airway disease which affects the lives of around 200 million people worldwide with an increasing incidence particularly in developing countries. The pathogenesis of COPD is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although cigarette smoking is the primary cause of this inflammation, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue repair and remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells (DCs). Little is known about the relative contribution of DCs in the pathogenesis of COPD. However the number of DCs is changed in smokers and COPD patients and cigarette smoke (CS) induces the release of chemokines from DCs that play a role in the pathogenesis of COPD. In this review paper, an overview is presented on the role of DCs and their mediators in the pathogenesis of COPD. The activation of DCs and their signaling in response to CS will also be highlighted and discussed.     

Regulatory T cells for immunotherapy of autoimmune diseases: from the bench to the bedside

The induction of antigen-specific unresponsiveness or tolerance is critical for the prevention of autoimmunity and maintenance of immune homeostasis. The presence of regulatory T cells (Treg cells) has been recently demonstrated in animals and in humans. Interestingly, Treg cells may be either quantitatively or qualitatively altered in human autoimmune diseases, for example, multiple sclerosis, psoriasis, Type 1 diabetes and inflammatory bowel disease (IBD), suggesting a role in disease pathophysiology. The present review summarises the emerging literature on the developmental origin and function of human Treg cells. The potential clinical application of Treg cells to human autoimmune diseases and to post-transplantation graft-versus-host disease is discussed.     

Regulatory and policy issues for T1DM immunotherapy

The development of immunotherapies for T1DM has lagged the development T2DM drugs, but with more clarity around regulatory requirements, large pharmaceutical companies have recently entered the field to support late stage programs. This clarity around regulatory expectations has emerged because of the convergence among regulators and clinical experts in how efficacy of these therapies should be assessed. The key agreement is that the primary efficacy endpoint for treatments directed at the underlying autoimmune cause of T1DM should be endogenous insulin secretion as reflected by standardized C-peptide measurements. Important secondary endpoints include glycemic control, total daily insulin dose, and hypoglycemia rates. Most T1DM therapeutic development efforts are directed at new onset disease, which represents a small proportion of the entire T1DM population. A new frontier in T1DM therapeutic development is emerging around combination treatment of established T1DM, a population that far outnumbers those with new onset T1DM. Fully effective therapies of new onset or established T1DM will almost certainly require a combination of two or more therapies. A T1DM prevention vaccine will not be feasible until after extensive experience with the agent as a treatment of new onset and/or established T1DM.     

Dendritic cell immunotherapy combined with cytokine-induced killer cells promotes skewing toward Th2 cytokine profile in patients with metastatic non-small cell lung cancer

Dendritic cell (DC) vaccination and cytokine-induced killer (CIK) cell therapy (DC/CIK) have shown limited success in the treatment of advanced non-small cell lung cancer (NSCLC). To investigate the reason for this limited success, the effects of DC/CIK cell therapy on the immune responses of tumor-bearing patients and patients with resected NSCLC were evaluated. In the total 50 patients studied, the serum concentrations of the Th2 cytokines (IL-4 and IL-10) in tumor-bearing patients were significantly higher than those with resected NSCLC before immunotherapy. The post-therapy Th1 cytokine (IFN-γ) level in patients with resected NSCLC significantly increased from the pre-therapy level. In contrast, significantly enhanced post-therapy Th2 cytokine (IL-4 and IL-10) levels were found in tumor-bearing patients. The intracellular staining assay revealed that DC/CIK cell therapy increased the IFN-γ-producing T lymphocyte (CD8⁺IFN-γ⁺) frequency in patients with resected NSCLC, but these lymphocytes were not found in tumor-bearing patients. Furthermore, overproduction of vascular endothelial growth factor (VEGF) in tumor-bearing patients showed a statistically positive correlation with IL-4, suggesting that VEGF might be responsible for the predominance of serum Th2 cytokines. In a word, tumor-bearing patients developed a Th2-dominant status that could not be reversed toward Th1 following immunotherapy. A combined regiment of DC vaccination and CIK cell therapy with other treatments to overcome systemic Th2-dominant immune response might improve the current clinical benefit.     

Modulation of regulatory T cells by intranasal allergen immunotherapy in an experimental rat model of airway allergy

Allergic airway diseases such as asthma and allergic rhinitis are increasing in prevalence worldwide. The theory of an altered Th1/Th2 balance in allergic diathesis has recently been termed a “procrustean paradigm” as it failed to explain many preclinical findings. Regulatory T cells (Treg) have now been shown to be critical in T-cell homeostasis and in the maintenance of peripheral tolerance to allergens. Allergen specific immunotherapy (SIT) has been shown to induce regulatory T cells in allergic patients. Among various types of SIT, intranasal immunotherapy had not been studied in detail for the treatment of allergic airway diseases. So, there was a need to study the contribution of regulatory T cells and their mechanistic pathways following intranasal immunotherapy in-vivo. It had been previously shown that intranasal allergen immunotherapy using Alstonia scholaris pollen extract abrogates allergic airway inflammation with decline in IgE and Th2 cytokine levels. The present study for the first time offers a multi-targeted approach towards attenuation of airway allergy by the generation of CD4 + CD25 + Foxp3 + T cells and other subsets of Treg cells like Tr1 cells, Th3 cells, CTLA4 + Treg cells, and also modulation of various Treg cell surface molecules like GITR, OX40, CD39 and CD73 by intranasal immunotherapy in the same animal model. This animal experiment will thus help to chart out newer molecular targets for treating allergic asthma or rhinitis.     

Dendritic cells in the pathophysiology of sarcoidal reactions

Dendritic cells play an important role in regulating both normal and pathophysiologic immune responses. Complicating the interpretation of dendritic cell function has been the observation that dendritic cells are not only rare, but can demonstrate multiple maturation/differentiation states. Despite these experimental limitations, the accumulating evidence suggests that dendritic cell are a dynamic migratory population that can be recruited into areas of peripheral inflammation. In the peripheral site of inflammation, dendritic cell function appears to involve the processing of antigen and its subsequent presentation to T lymphocytes. Dendritic cells also appear to be capable of transporting antigen to the regional lymph node through the afferent lymphatics. Dendritic cells can be found in the paracortex where they appear to be interacting with T lymphocytes to provide both membrane-bound and soluble activation signals. The central regulatory role of the dendritic cell in immune responses suggests that sarcoidal reactions, and other mononuclear inflammatory processes, are likely to be clinical entities that reflect perturbed dendritic cell function.     

Dendritic cells and oral transmission of prion diseases

Transmissible spongiform encephalopathies (scrapie, BSE, Kuru) develop as central nervous system (CNS) diseases after long incubation periods, and many of which may arise following the consumption of infected material. The infectious agent is thought to be a misfolded form (scrapie associated PrP (PrP(Sc))) of a normal host protein (cellular isoform of PrP (PrP(C))), which is relatively resistant to proteolytic degradation and which serves as a template, directing host prion protein (PrP) to accumulate in the misfolded form. Animal experiments have shown that CNS disease is preceded by a period in which the agent accumulates in secondary lymphoid organs (Peyer's patches (PP), lymph nodes, spleen), particularly follicular dendritic cells (FDCs) in the B cell areas of these organs. How the agent is transmitted from the intestinal lumen to the FDCs is largely unknown. Dendritic cells (DCs, cells quite distinct from FDCs) are cells that are specialised to acquire antigens from peripheral tissues and to transport them to secondary lymphoid organs for presentation to T and B lymphocytes. We have shown that DCs can acquire PrP(Sc) from the intestinal lumen and deliver it to mesenteric lymph nodes. In this review we discuss the different stages involved in the migration of PrP(Sc) from the intestine to FDCs and consider the different stages and barriers involved in this process. We conclude that transport of the causative agent, using PrP(Sc) as a biomarker, from the intestine to FDCs is a very inefficient process, which may help to account for the apparent low frequency of individuals who have consumed infected material that go on to develop clinical disease.     

Dendritic cells and skin sensitisation hazard assessment.

Allergic contact dermatitis is an important occupational and environmental health disease. There is a need, therefore, to identify skin sensitisation hazard, and to assess accurately likely risks to human health. During the past 15 years very significant advances have been made in our understanding of the cellular and molecular mechanisms that serve to initiate and regulate cutaneous immune responses, including the acquisition of skin sensitisation. This has facilitated parallel advances in the identification and characterisation of skin sensitising chemicals and the development of more robust approaches to risk assessment. It is relevant to consider whether advances in immunobiology provide opportunities also for the design of alternative approaches to the toxicological evaluation of skin sensitisation, including the development of in vitro methods. Here we review the potential use of strategies based on analysis of responses induced in Langerhans cells and dendritic cells; professional antigen processing and presenting cells that are known to play pivotal roles during the induction phase of adaptive immune responses.     

T细胞受体基因修饰在过继免疫治疗中的应用

T细胞过继性转移可以增强免疫系统介导的对肿瘤细胞的消除,是近年来获得较高关注的一种特异性、无毒性的癌症新疗法,此方法对于治疗血液性和实体恶性肿瘤具有一定效果。对T细胞进行基因修饰能够增强其免疫能力,保持T细胞的持久活性,同时也可以克服肿瘤自身的免疫逃避机制,潜在提高免疫治疗应用于多种肿瘤疾病的成功率。在T细胞过继转移中,T细胞受体(TCR)基因转移作为一种发展迅速的免疫治疗方法,可以在体外产生大量的具有已知抗原特异性和功能亲和性的T细胞,应用于病毒感染或病毒相关恶性肿瘤的过继细胞免疫治疗。TCR基因转移利用逆转录病毒或慢病毒作为载体,其中包含了从所需抗体特异性T细胞群中克隆得到的TCR-α和TCR-β链基因序列,然后应用TCR编码载体转导体外的原始T细胞。为产生带有所需功能特异性的转导T细胞,引入的TCR-α和TCR-β链必须形成异源二聚体,与CD3复合体结合从而在T细胞表面稳定表达。     

特异性免疫治疗对哮喘大鼠白细胞介素-10和CD_4~＋CD_（25）~＋调节性T细胞的影响

目的：探讨特异性免疫治疗（specific immunotherapy,SIT）对哮喘大鼠白细胞介素-10（IL-10）和CD4＋CD25＋调节性T细胞（CD4＋CD25＋Tr）的影响。方法：40只健康雄性清洁级Wistar大鼠随机均分成正常对照组、哮喘组、SIT对照组和SIT治疗组,每组10只。通过卵蛋白（OVA）雾化吸入的方法对致敏大鼠进行SIT干预,观察各组支气管肺泡灌洗液（BALF）中细胞分类及计数结果、血清和BALF中IL-10水平及外周血CD4＋CD25＋Tr百分率变化。结果：正常对照组BALF和血清中IL-10浓度分别高于哮喘组和SIT对照组（均为P〈0.01）,哮喘组和SIT对照组BALF和血清中IL-10浓度低于SIT治疗组（P〈0.01,P〈0.05）;正常对照组外周血CD4＋CD25＋Tr百分率显著高于哮喘组、SIT对照组和SIT治疗组（P〈0.01）,而SIT治疗组CD4＋CD25＋Tr百分率分别高于哮喘组和SIT对照组（P〈0.05）。结论：通过上调体内IL-10和CD4＋CD25＋Tr趋于正常状态可能是SIT治疗哮喘有效的重要机制。