基于打破树突状细胞耐受的抗肿瘤免疫治疗

树突状细胞(DC)是专职抗原呈递细胞,具有强大的免疫监视功能.由于在诱导免疫反应中的重要作用,DC已被广泛地应用于抗肿瘤免疫治疗.但是由于肿瘤细胞对荷瘤宿主免疫系统,尤其是对DC功能的抑制,使以DC为基础的抗肿瘤免疫治疗疗效受到了很大的限制.所以,通过调节DC功能,可打破肿瘤对DC的免疫抑制,引导有效的抗肿瘤反应,提高以DC为基础的抗肿瘤免疫效果,这在抗肿瘤免疫治疗中具有重要意义.     

低剂量电离辐射诱导的兴奋性效应—肿瘤免疫治疗的新希望

低剂量电离辐射(LDR)诱导的兴奋性效应(hormesis)能增强受照机体的固有免疫和适应性免疫反应.以树突状细胞(DC)为基础的肿瘤免疫治疗开始于20世纪60年代,实验证实免疫治疗能在某种程度上提升抗肿瘤免疫应答和抑制肿瘤生长和转移.通过总结分析近几年的文献报道,可了解兴奋性效应增强免疫治疗临床效果的可能性.     

028 树突状细胞与特异性肿瘤免疫治疗

树突状细胞(DC)是体内功能最强的抗原提呈细胞(APC),也是抗原特异性免疫应答的始动者,由DC激活的T细胞介导的免疫应答在机体抗肿瘤过程中起着主导作用.本文主要对DC参与抗肿瘤的机制、DC与肿瘤免疫逃逸的关系及近年来DC在肿瘤生物治疗方面的研究进展作一综述.以DC为基础的肿瘤治疗主要有两种方式①免疫治疗肿瘤抗原体外冲击致敏DC后回输体内;②基因治疗以目的基因转染DC后回输体内.     

树突状细胞直接抗肿瘤作用研究进展

树突状细胞(DC)是功能最强的抗原递呈细胞,其除可将肿瘤抗原递呈给T细胞以间接杀伤肿瘤细胞外,还可作为效应细胞直接发挥抗肿瘤作用.DC可通过细胞间接触和分泌细胞因子直接抑制肿瘤细胞的增殖,并可通过与TNF家族密切相关的凋亡通路直接杀伤敏感肿瘤细胞.DC的这一固有免疫功能在肿瘤免疫治疗中具有重要的意义.     

树突状细胞与肿瘤免疫

树突状细胞 ( Dendritic Cell,DC)是一种重要的抗原提呈细胞 ( APC) ,能强有力地激发静息的T细胞 ,是体内激活幼稚 T细胞的主要 APC。近年来 ,DC的抗肿瘤免疫作用及其肿瘤免疫治疗中的应用倍受关注。本文对 DC的免疫学特性 ,DC与肿瘤的关系及其抗肿瘤作用和在肿瘤免疫治疗中的应用最新研究进展作一综述。     

针对MUC1黏蛋白DC疫苗的研究进展

树突状细胞(DC)作为抗原递呈细胞在激活肿瘤特异性免疫中发挥重要作用,DC疫苗为肿瘤免疫治疗提供了一种有效手段.MUC1是一种高分子量糖蛋白,属于粘蛋白家族成员,在多种上皮性肿瘤中异常表达,是肿瘤免疫治疗的理想靶抗原.本文综述了MUC1的生物学特征、DC对MUC1的递呈和以MUC1为靶点DC疫苗的抗肿瘤效果.     

树突状细胞与特异性肿瘤免疫治疗

树突状细胞 (DC)是体内功能最强的抗原提呈细胞 (APC) ,也是抗原特异性免疫应答的始动者 ,由DC激活的T细胞介导的免疫应答在机体抗肿瘤过程中起着主导作用。本文主要对DC参与抗肿瘤的机制、DC与肿瘤免疫逃逸的关系及近年来DC在肿瘤生物治疗方面的研究进展作一综述。以DC为基础的肿瘤治疗主要有两种方式 :①免疫治疗 :肿瘤抗原体外冲击致敏DC后回输体内 ;②基因治疗 :以目的基因转染DC后回输体内     

树突状细胞疫苗在肿瘤免疫治疗领域的研究现状

树突状细胞 (DendriticCells ,DC)是目前所知的功能最强的、也是唯一能激活初始性T细胞 (NativeTcell)的专职抗原提呈细胞 (AntigenPresentingCell,APC) ,具有强大的激活CD8+ CTL及CD4 + T辅助细胞的能力 ,控制着体内免疫反应的过程 ,在免疫应答中处于中心地位 ,因而成为肿瘤免疫反应的中心环节。DC可以在体外培养后用于体内免疫治疗 ,也可辅以细胞因子或其它因子如Flt 3等在体内扩增[1] 。用DC疫苗进行抗肿瘤治疗已受到重视[2 ,3 ] ,且成为当今肿瘤生物治疗领域备受关注的热点课题 ,对树突状细胞疫苗的研究日趋深入而广泛。1　…     

逆转T 细胞耗竭在肿瘤免疫治疗中研究进展

近年来随着肿瘤免疫治疗的深入研究,PD-1/PD-L1免疫抑制剂在临床试验及临床实际抗肿瘤应用中取得突破性进展,但仍有临床耐药及部分患者无效的问题,PD-1/PD-L1免疫抑制剂抗肿瘤机制主要为改善抗肿瘤免疫应答,逆转T细胞耗竭,增强T细胞抗肿瘤免疫反应。本文以逆转T细胞耗竭最新研究及进展应用于肿瘤免疫治疗作一综述,为临床治疗提供参考。     

调节性T细胞介导的肿瘤免疫耐受

恶性肿瘤能够有效的逃避免疫系统的监视源于免疫反应系统功能的障碍,多种因素都可导致抗肿瘤免疫的失效.调节性T细胞(Tr)在肿瘤浸润的淋巴细胞及肿瘤引流的淋巴结中高频出现,意味着其能促进肿瘤生长.Tr在肿瘤免疫病理以及调节免疫治疗的效果中起重要作用.因此,肿瘤患者的Tr可能成为重要的治疗靶细胞,并将会为抗肿瘤免疫治疗提供新策略.     

The site of tumor development determines immunogenicity via temporal mobilization of antigen‐laden dendritic cells in draining lymph nodes

The elimination of solid tumors largely depends on effective T‐cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC‐rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i.d.), but not s.c. tumors are rapidly rejected in a T‐cell‐dependent manner and induce protective T‐cell responses. The rejection of i.d. tumors correlates with rapid recruitment of dermal DCs presenting the tumor antigen to both CD4 and CD8 T cells in the draining lymph nodes (dLNs). The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Altogether, our results show that the anatomical site of tumor development influences tumor immunogenicity, notably by controlling the kinetics of DC mobilization in the draining LNs.     

Cellular immunotherapy with dendritic cells in cancer: current status

Dendritic cells (DCs) are specialized antigen-presenting cells whose immunogenicity leads to the induction of antigen-specific immune responses. DCs can easily be generated ex vivo from peripheral blood monocytes or bone marrow/circulating hematopoietic stem cells cultured in the presence of cytokine cocktails. DCs have been used in numerous clinical trials to induce antitumor immune responses in cancer patients. The studies carried out to date have demonstrated that DCs pulsed with tumor antigens can be safely administered, and this approach produces antigen-specific immune responses. Clinical responses have been observed in a minority of patients. It is likely that either heavy medical pretreatment or the presence of large tumor burdens (or both) is among the causes that impair the benefits of vaccination. Hence, the use of DCs should be considered in earlier stages of disease such as the adjuvant setting. Prospective applications of DCs extend to their use in allogeneic adoptive immunotherapy to specifically target the graft versus tumor reaction. DCs continue to hold promise for cellular immunotherapy, and further investigation is required to determine the clinical settings in which patients will most benefit from the use of this cellular immune adjuvant.     

Dendritic cell as therapeutic vaccines against tumors and its role in therapy for hepatocellular carcinoma

Dendritic cells （DCs） are the most potent professional antigen-presenting cells, and capable of stimulating naive T cells and driving primary immune responses. DCs are poised to capture antigen, migrate to draining lymphoid organs, and after a process of maturation, select antigen-specific lymphocytes to which they present the processed antigen, thereby inducing immune responses. The development of protocols for the ex vivo generation of DCs may provide a rationale for designing and developing DC-based vaccination for the treatment of tumors. There are now several strategies being applied to upload antigens to DCs and manipulate DC vaccines. DC vaccines are able to induce therapeutic and protective antitumor immunity. Numerous studies indicated that hepatocellular carcinoma （HCC） immunotherapies utilizing DC-presenting tumor-associated antigens could stimulate an antitumour T cell response leading to clinical benefit without any significant toxicity. DC-based tumor vaccines have become a novel immunoadjuvant therapy for HCC. Cellular ＆ Molecular Immunology. 2006;3（3）：197-203.     

Human regional lymph nodes draining cancer exhibit a profound dendritic cell depletion as comparing to those from patients without malignancies

Dendritic cells (DCs) are bone-marrow derived 'professional' antigen presenting cells (APC). They are considered as the most potent APC able to induce primary immune responses. DC efficiently capture and process proteic and non-proteic antigens. They are widely distributed throughout the body and occupy sentinel positions such as epithelia. Establishment of an immune response against cancer may depend of the capacity of DCs to transfer (to capture, to process and to present) tumor antigens into regional lymph nodes where they can induce a specific response leading to tumor rejection. Because host 'professional' DCs are one of the most important elements in the induction of specific anti-tumor responses and lymph nodes are the places where the immune response takes place, we investigated the densities of DCs within regional metastasis-free lymph nodes from 47 patients with different malignant epithelial tumors as comparing with lymph nodes from 11 patients without malignancies using an immunohistochemistry method with anti-S100 protein, CD86 and CD1a antibodies. By means of morphometric analysis, we observed that S100+ and CD1a+ DCs densities in regional lymph nodes from cancer patients were significatively decreased as compared with control lymph nodes (P<0.0001 and 0.003, respectively). S100+ DCs and CD86+ DCs densities in lymph nodes draining cancer were similar. Taken together, these data indicated that lymph nodes draining cancer had significantly less CD1a+ DCs than S100+ and possibly CD86+ DCs. These findings may represent another mechanism by which tumors evade the immune recognition.     

Induction of T cell responses against autologous ovarian tumors with whole tumor cell lysate-pulsed dendritic cells.

The loading of dendritic cells (DCs) with whole tumor cell lysates may circumvent the facts that few tumor-specific antigens have been identified in human solid tumors. The present study was designed to investigate whether ovarian cancer cells lysate-pulsed DCs activate T cell responses against autologous ovarian tumors. Incubation of T cells with autologous tumor cell lysate-pulsed DCs stimulated proliferation of autologous T cells. T cells primed by autologous tumor cell lysate-pulsed DCs showed significant killing activity against autologous tumor cells, which could be blocked by anti-MHC-class-I and anti-CD8 mAb. By contrast, T cells primed by autologous unpulsed DCs alone or tumor lysates alone failed to exhibit significant killing activity. In addition, T cells primed by DCs pulsed with allogeneic tumor cell lysates or with autologous normal cell lysate or by these cell lysates alone did not induce the increase in the autologous tumor killing activity. As additional controls, T cells stimulated with autologous tumor lysate-pulsed DCs express no increase in the lysis of autologous monocytes, allogeneic ovarian tumor cells and other cell lines including K562, Daudi and Molt-4. Furthermore, T cells stimulated with autologous tumor lysate-pulsed DCs could produce the considerable amounts of cytokines such as GM-CSF, TNF-alpha and IFN-gamma. The data in the present study suggest that whole tumor cell lysates-pulsed DCs could activate T cell responses against autologous ovarian tumor cells, and that these pulsed DCs may be used as a new approach for the specific immunotherapy of ovarian cancer patients.     

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses. TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response. The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer (NK) cells. However, the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear, and different TLR7/8 agonists have been found to induce different responses. In this study, we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes, stimulate the activation of splenic T, NK and natural killer T (NKT) cells, increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines, and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells (DCs). In a murine model, both agonists improved the antitumor effects of tumor lysate-loaded DCs, resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis. Further, we found that gardiquimod demonstrated more potent antitumor activity than imiquimod. These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy. More importantly, they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.     

Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy

Dendritic cell (DC)-based vaccines continue to be considered an attractive tool for cancer immunotherapy. DCs require an additional signal from the environment or other immune cells to polarize the development of immune responses toward T helper 1 (Th1) or Th2 responses. DCs play a role in natural killer (NK) cell activation, and NK cells are also able to activate and induce the maturation of DCs. We investigated the types of NK cells that can induce the maturation and enhanced function of DCs and the conditions under which these interactions occur. DCs that were activated by resting NK cells in the presence of inflammatory cytokines exhibited increased expression of several costimulatory molecules and an enhanced ability to produce IL-12p70. NK cell-stimulated DCs potently induced Th1 polarization and exhibited the ability to generate tumor antigen-specific cytotoxic T lymphocyte responses. Our data demonstrate that functional DCs can be generated by coculturing immature DCs with freshly isolated resting NK cells in the presence of Toll-like receptor agonists and proinflammatory cytokines and that the resulting DCs effectively present antigens to induce tumor-specific T-cell responses, which suggests that these cells may be useful for cancer immunotherapy.     

B cells as a cellular adjuvant: induction or control of T-cell immunity--or both?

Evaluation of: Reichhardt P, Dornbach B, Rong S et al. Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse. Blood 110 (5), 1519-1529 (2007). Cellular adjuvants, such as dendritic cells (DCs) are in the focus of tumor immunology and immunotherapy as tools to enhance immune responses in order to control cancer. Recent observations suggest that so-called tolerogenic DCs can be employed to achieve the opposite--the control of adverse immune reactions in transplantation or autoimmunity. However, the use of DCs is limited due to their low frequency, lack of purity and expansion in cell culture. Activated B cells have previously been shown to efficiently present antigen and be expandable to almost unlimited amounts, rendering them an interesting alternative to induce antitumor immune responses. The paper under evaluation extends this concept to B cells as tolerogenic cells by providing insight in a novel mechanism--the induction of regulatory T cells.     

Effect of laminin environments and tumor factors on the biology of myeloid dendritic cells

Dendritic cells (DCs) are immune cells that surveil the organism for infections or malignancies and activate specific T lymphocytes initiating specific immune responses. Contrariwise, DCs have been show to participate in the development of diseases, among them some types of cancer by inducing angiogenesis or immunosuppression. The ultimate fate of DC functions regarding their role in disease or health is prompted by signals from the microenvironment. We have previously shown that the interaction of DCs with various extracellular matrix components modifies the immune properties and angiogenic potential of these cells.The objective of the current studies was to investigate the angiogenic and immune profile of murine myeloid DCs upon interaction with laminin environments, with a particular emphasis on ovarian cancer.Our results show that murine ovarian tumors produce several types of laminins, as determined by PCR analysis, and also that tumor-associated DCs, both from ascites or solid tumors express adhesion molecules capable of interacting with these molecules as determined by flow cytometry and PCR analysis. Further, we established that DCs cultured on laminin upregulate both AKT and MEK signaling pathways, and that long-term culture on laminin surfaces decreases the immunological capacities of these cells when compared to the same cells cultured on synthetic substrates. In addition, we observed that tumor conditioned media was able to modify the metabolic status of these cells, and also reprogram the development of DCs from bone marrow precursors towards the generation of myeloid-derived suppressor cells.Overall, these studies demonstrate that the interaction between soluble factors and extracellular matrix components of the ovarian cancer microenvironment shape the biology of DCs and thus help them become co-conspirators of tumor growth.