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      Tetanus toxoid and CCL3 improve DC vaccines in mice and glioblastoma patients

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          Abstract

          Upon stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses 1 . As such, autologous DCs generated ex vivo have been pulsed with tumor antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers 24 including glioblastoma (GBM), 57 the factors dictating DC vaccine efficacy remain poorly understood. Here we demonstrate that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumor antigen-specific DCs. To assess the impact of vaccine site pre-conditioning in humans, we randomized patients with GBM to pre-conditioning with mature DCs 8 or Td unilaterally before bilateral vaccination with Cytomegalovirus pp65 RNA-pulsed DCs. We and other laboratories have shown that pp65 is expressed in > 90% of GBM specimens but not surrounding normal brain 912 , providing an unparalleled opportunity to subvert this viral protein as a tumor-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumor growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve antitumor immunotherapy.

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          Most cited references 23

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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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            Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction.

            CD8+ T cells have a crucial role in resistance to pathogens and can kill malignant cells; however, some critical functions of these lymphocytes depend on helper activity provided by a distinct population of CD4+ T cells. Cooperation between these lymphocyte subsets involves recognition of antigens co-presented by the same dendritic cell, but the frequencies of such antigen-bearing cells early in an infection and of the relevant naive T cells are both low. This suggests that an active mechanism facilitates the necessary cell-cell associations. Here we demonstrate that after immunization but before antigen recognition, naive CD8+ T cells in immunogen-draining lymph nodes upregulate the chemokine receptor CCR5, permitting these cells to be attracted to sites of antigen-specific dendritic cell-CD4+ T cell interaction where the cognate chemokines CCL3 and CCL4 (also known as MIP-1alpha and MIP-1beta) are produced. Interference with this actively guided recruitment markedly reduces the ability of CD4+ T cells to promote memory CD8+ T-cell generation, indicating that an orchestrated series of differentiation events drives nonrandom cell-cell interactions within lymph nodes, optimizing CD8+ T-cell immune responses involving the few antigen-specific precursors present in the naive repertoire.
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              Regulation of Dendritic Cell Migration to the Draining Lymph Node

              Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7−/− DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor necrosis factor that conditioned the tissue for increased DC migration. These results indicate that DC number and tissue inflammation are critical parameters for DC-based vaccination.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                18 February 2015
                11 March 2015
                19 March 2015
                19 September 2015
                : 519
                : 7543
                : 366-369
                Affiliations
                [1 ]Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC
                [2 ]Division of Neurosurgery, Duke University Medical Center, Durham, NC
                [3 ]Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, NC
                [4 ]Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC
                [5 ]Department of Immunology, Duke University Medical Center, Durham, NC
                [6 ]Department of Pathology, Duke University Medical Center, Durham, NC
                [7 ]Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC
                [8 ]Department of Radiation Oncology, Duke University Medical Center, Durham, NC
                Author notes
                [a ]Corresponding Authors: John H. Sampson, M.D., Ph.D., M.H.Sc., M.B.A., Preston Robert Tisch Brain Tumor Center at Duke, Chief, Division of Neurosurgery, DUMC Box 3050, 303 Research Drive, 220 Sands Building, Duke University Medical Center, Durham, North Carolina 27710, USA, john.sampson@ 123456duke.edu , Phone: (919) 684-9041, Fax: (919) 684-9045, Duane A. Mitchell, M.D., Ph.D., Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, Department of Neurosurgery, PO Box 100265, MBI Room L1-181, University of Florida, Gainesville, FL 32605, duane.mitchell@ 123456neurosurgery.ufl.edu , Phone: (352) 294-5232, Fax: (352) 392-3252
                [*]

                These authors contributed equally to this work.

                Article
                NIHMS664586
                10.1038/nature14320
                4510871
                25762141

                Reprints and permissions information is available at www.nature.com/reprints.

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