Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity (original) (raw)
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Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies
Expert Review of Vaccines, 2013
Dendritic cells (DCs) are specialized immunostimulatory cells involved in the induction and regulation of immune responses. The feasibility of large-scale ex vivo generation of DCs from patients' monocytes allows for therapeutic application of ex vivo-cultured DCs to bypass the dysfunction of endogenous DCs, restore immune surveillance, induce cancer regression or stabilization or delay or prevent its recurrence. While the most common paradigm of the therapeutic application of DCs reflects their use as cancer 'vaccines', additional and potentially more effective possibilities include the use of patients' autologous DCs as parts of more comprehensive therapies involving in vivo or ex vivo induction of tumor-reactive T cells and the measures to counteract systemic and local immunosuppression in tumor-bearing hosts. Ex vivocultured DCs can be instructed to acquire distinct functions relevant for the induction of effective cancer immunity (DC polarization), such as the induction of different effector functions or different homing properties of tumor-specific T cells (delivery of 'signal 3' and 'signal 4'). These considerations highlight the importance of the application of optimized conditions for the ex vivo culture of DCs and the potential combination of DC therapies with additional immune interventions to facilitate the entry of DC-induced T cells to tumor tissues and their local antitumor functions.
Dendritic cells vaccines: Immunotherapy against cancer
2020
Dendritic cells are specialized cells of the innate immune system, with high capacity to present antigens in the context of the Major Histocompatibility Complex II (MHC-II) to T lymphocytes (CD4+); these cells are up to 100 times stronger than any other antigen presenting cell. The ability of the antigen presentation by dendritic cells has been documented in animal models and clinical studies conducted in humans. Based on the above, different techniques and methods have been developed to use dendritic cells in cancer-aimed immunotherapies. The dendritic cell vaccines refer to biological therapies, prepared by different strategies (ex vivo and in vivo), which aim to enhance the presentation of tumor antigens and develop a more targeted and sustained immune response on these. They are obtained from precursor cells that mature with specific stimuli that direct them to the desired therapy. Different applications for these therapies have been described in numerous types of cancers, which...
Plasmacytoid dendritic cells and cancer
2011
Cancer develops in a complex microenvironment comprising cancer cells, stromal cells, and host immune cells with their soluble products. The counteracting host-protective and tumor-promoting roles of different immune cell populations have been elegantly clarified in the last decade by pertinent genetically modified mouse models. Among cells with a potential role in cancer immunity, PDCs might represent important players as a result of their capacity to bring together innate and adaptive immunity. This review summarizes current knowledge about the role of PDCs in cancer immunity. PDCs have been documented in primary and metastatic human neoplasms; however, the clinical significance of this finding is still unknown. Once into the tumor bed, PDCs can be hijacked by the tumor microenvironment and lose their propensity to produce the required amount of endogenous I-IFN. However, when properly reprogrammed (i.e., by TLR agonists), PDCs might mediate tumor rejection in a clinical setting. Tumor rejection, at least partially, is driven by I-IFN and seems to require a cross-talk with other innate immune cells, including IFN DCs. The latter evidence, although still limited to skin cancers, can provide a leading model for developing adjuvant immune therapy for other neoplasms. To this end, the generation of appropriate mouse models to modulate the frequency and activation state of murine PDCs will also be of remarkable importance.
Dendritic Cells in Cancer Immunotherapy
Annual Review of Immunology, 2000
Dendritic cells (DCs) play a central role in the initiation and regulation of innate and adaptive immune responses and have increasingly been applied as vaccines for cancer patients. Ex vivo generation and antigen loading of monocyte-derived DCs allows a controlled maturation, with the aim of imprinting different DC functions that are essential for their subsequent induction of a T cell-mediated anti-tumor response. A better understanding of how DCs control T cell immunity is important for the design of novel DC-based cancer vaccines with improved clinical efficiency. The aim of this thesis was to evaluate how different maturation conditions used for generation of clinical grade DC-based cancer vaccines affect their capacity to assist type-1 polarized immune responses, important for elimination of cancer.
Dendritic cells in cancer vaccines
Experimental Hematology, 2001
Dendritic cells (DC) are recognized as the most potent antigen-presenting cells with the ability to stimulate naive resting T cells and to initiate primary immune responses. Encouraging results in vaccination studies in animal models and the development of protocols to generate sufficient numbers of human DC for clinical application have led to attempts to verify the feasibility and efficacy of this approach in patients in the context of Phase I/II vaccination trials. This review aims to present a concise overview of the current knowledge in DC development and biology and describes the recent data of the first published DC-based vaccination studies. These preliminary trials indicate that immunotherapies utilizing DC-presenting tumor-associated antigens can safely be administered to patients with cancer and induce significant immunologic and clinical responses.
Clinical application of dendritic cells in cancer vaccination therapy
APMIS, 2003
During the last decade use of dendritic cells (DC) has moved from murine and in vitro studies to clinical trials as adjuvant in cancer immunotherapy. Here they function as delivery vehicles for exogenous tumor antigens, promoting an efficient antigen presentation. The development of protocols for large-scale generation of dendritic cells for clinical applications has made possible phase I/II studies designed to analyze the toxicity, feasibility and efficacy of this approach. In clinical trials, DC-based vaccination of patients with advanced cancer has in many cases led to immunity and in selected patients to tumor regression. However, the majority of clinical trials are still in phase I, and interpretations are hampered by pronounced variation in study design related to technical aspects of DC preparation, treatment and schedule, monitoring of immune response, and clinically relevant endpoints, including toxicity and response evaluation. This paper aims to review the technical aspects and clinical impact of vaccination trials, focusing on the generation of DC-based vaccines, evaluation of immunologic parameters and design of clinical trials necessary to meet the need for good laboratory and clinical practice.
Dendritic Cell-Based Vaccines in Cancer
American Journal of Cancer, 2002
Therapeutic vaccines that can activate the immune system to destroy malignancies hold the promise of a low-toxicity, precisely targeted anticancer treatment modality. Because dendritic cells (DCs) are central to the activation of antigen-specific immune responses, DCs loaded with tumor antigens are of considerable interest as therapeutic vaccines. Preclinical studies have demonstrated the potency of DC-based immunizations in promoting tumor rejection. Continued preclinical and clinical studies are assessing a number of important parameters regarding the formulation and administration regimen of DC-based vaccines and have provided support for phase I and II studies. Thus far, DC-mediated immunizations have been well tolerated, with few toxicities reported. Tumor regression has been reported in up to 30% of patients, particularly with immunologically sensitive tumors such as melanoma. Biologic activity, measured as activation of antigen-specific T cells, is reported in up to 100% of patients immunized against potent recall antigens, such as tetanus toxoid, and up to 30% of those immunized against tumor antigens. Current clinical trials are increasingly testing DC-based vaccines in patients with minimal residual disease, such as following attempted curative surgery or following high-dose chemotherapy and stem-cell support where clinical benefit is likely to be the greatest. Newer strategies are focusing on further modifications to DCs to increase their immunostimulatory potency. These include newer methods of antigen loading, better techniques for DC maturation, strategies to enhance polarization of DCs to ensure the induction of T helper cell type 1 immune responses, and the administration of adjunctive cytokines to augment the immune response following immunization.
Pharmaceutics
Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their developm...
The Role of Plasmacytoid Dendritic Cells in Cancers
Frontiers in Immunology, 2021
Plasmacytoid dendritic cells (pDCs) are a special subtype of dendritic cells with the morphology of plasma cells. pDCs produce massive amounts of type I interferon (IFN-I), which was originally found to play an extremely pivotal role in antiviral immunity. Interestingly, accumulated evidence indicates that pDCs can also play an important role in tumorigenesis. In the human body, most of the IFN-α is secreted by activated pDCs mediated by toll-like receptor (TLR) stimulation. In many types of cancer, tumors are infiltrated by a large number of pDCs, however, these pDCs exhibit no response to TLR stimulation, and reduced or absent IFN-α production. In addition, tumor-infiltrating pDCs promote recruitment of regulatory T cells (Tregs) into the tumor microenvironment, leading to immunosuppression and promoting tumor growth. In this review, we discuss recent insights into the development of pDCs and their roles in a variety of malignancies, with special emphasis on the basic mechanisms.