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      Dendritic Cell-Specific Delivery of Flt3L by Coronavirus Vectors Secures Induction of Therapeutic Antitumor Immunity


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          Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs). Here, we assessed antitumor immunity induced by attenuated coronavirus vectors which exclusively target DCs in vivo and express either lymphocyte- or DC-activating cytokines in combination with a GFP-tagged model antigen. Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15. Moreover, Flt3L vectors more efficiently induced tumor-specific CD8 + T cells, expanded the epitope repertoire, and provided both prophylactic and therapeutic tumor immunity. In contrast, IL-2- or IL-15-encoding vectors showed a substantially lower efficacy in CD8 + T cell priming and failed to protect the host once tumors had been established. Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity.

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          Most cited references43

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          Taking dendritic cells into medicine.

          Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.
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            T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.

            Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.
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              The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design.

              Interleukin-2 and interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin-2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin-15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. As discussed in this Review, the biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                28 November 2013
                : 8
                : 11
                : e81442
                [1 ]Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
                [2 ]Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [3 ]Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
                Leiden University Medical Center, Netherlands
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BL. Performed the experiments: CPS CGC MN EA LCB RZ. Analyzed the data: BL CPS CGC. Wrote the manuscript: BL CPS CGC.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 26 August 2013
                : 22 October 2013
                This study received financial support from the Wilhelm Sander Foundation (to B.L.) and through the TOLERAGE project funded by the European Commission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article



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