Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state

Department of Tumor Immunology, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands.
Cancer Research (Impact Factor: 9.33). 02/2003; 63(1):12-7.
Source: PubMed


Dendritic cells are the professional antigen-presenting cells of the immune system. To induce an effective immune response, these cells should not only express high levels of MHC and costimulatory molecules but also migrate into the lymph nodes to interact with naïve T cells. Here, we demonstrate that in vitro-generated mature, but not immature dendritic cells, efficiently migrate into the T-cell areas of lymph nodes of melanoma patients. This difference is confirmed by in vitro studies, in which immature dendritic cells are strongly adherent, whereas mature dendritic cells remain highly motile. Our present findings demonstrate that the ability of dendritic cells to mount a proper immune response correlates with their ability to migrate both in vitro and in vivo.

Download full-text


Available from: Gosse J Adema,
  • Source
    • "DCs are already activated and therefore they are able to migrate to the secondary lymph nodes wherein they will trigger T cells. However, the relative short half-life of TAA-MHC complexes on DC membrane surface, and the low percentage (3–5%) of DCs that can migrate to the lymph nodes and contact with T cells can contribute to the low rate of success of these vaccines (De Vries et al., 2003; Hamdy et al., 2011). Also, being produced specifically for a particular patient, ex vivo DC-based vaccines are a highly complex, laborious, time-consuming and expensive approach. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.
    Frontiers in Chemistry 11/2014; 2(105):1. DOI:10.3389/fchem.2014.00105
  • Source
    • "The initial success of the CTLA-4 and PD-1 “checkpoint” immunotherapies motivated researchers to expand their investigations into targeting other known cosignalling receptors as potential agonistic immunotherapies. In particular, members of the tumor necrosis factor receptor super family (OX40, 4-1BB, and GITR) whose role as costimulatory receptors help maintain survival, effector function, and memory persistence of activated T cells [74]. Extensive preclinical studies indicate that agonistic OX40 therapy can promote antitumor immunity by simultaneously expanding effector T cells while blocking Treg mediated suppression [75–80], particularly when delivered intratumourally [79]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumorsmay be more effective, particularly those that overcomenatural suppressive factors in the tumor microenvironment.The“TrojanHorse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.
    Research Journal of Immunology 05/2014; 2014. DOI:10.1155/2014/789069
  • Source
    • "Since intravenously (i.v.) injected, ex vivo generated DCs fail to induce potent skin-homing T cells in mice and appeared to be less efficient in inducing TH1 responses in humans, previous clinical trials focused on subcutaneous or intradermal (i.d.) administration of the vaccines (60–62). However, using 111In-labeling and scintigraphy, we could show that most of the injected DCs remain at the injection site, where they rapidly die to be phagocytosed by macrophages (42, 63, 64). Pretreatment of the skin with cytokines, toll-like receptor (TLR) ligands, or activated DCs did not lead to increased migration (64). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cell (DC)-based immunotherapy employs the patients' immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells.
    Frontiers in Immunology 04/2014; 5:165. DOI:10.3389/fimmu.2014.00165
Show more