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Dendritic cell vaccines containing lymphocytes produce improved immunogenicity in patients with cancer

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      Abstract

      Background

      Dendritic cells are currently under investigation for their ability to generate anti-cancer immune responses. No consensus has been reached as to the optimal method of dendritic cell vaccine preparation and is a barrier to success in the field.

      Methods

      Over a course of three separate dendritic cell vaccine studies to treat cancer, we tested two different methods for preparing dendritic cells from peripheral blood mononuclear cells: adherence and antibody-selected CD14+ cells.

      Results

      Surprisingly, we found that patients who received dendritic cell vaccines generated by the adherence method mounted increased T cell proliferation in response to vaccination. This difference could not be accounted for by dendritic cell vaccine dose, cell surface phenotype or dendritic cell function in vitro. One notable difference between the two vaccine preparation methods was that the dendritic cell vaccine cultures generated by the adherence method contained up to 10% lymphocytes, and these lymphocytes were proliferating and producing IFNγ in response to antigen in vitro at the time of administration.

      Conclusions

      Enhanced immunogenicity of adherence dendritic cell vaccinations may be due to the presence of lymphocytes during dendritic cell culture.

      Trial registration

      Clinicaltrials.gov identifiers: NCT00289341, NCT00345293, and NCT00893945

      Electronic supplementary material

      The online version of this article (doi:10.1186/s12967-014-0338-3) contains supplementary material, which is available to authorized users.

      Related collections

      Most cited references 22

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      Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha

      Using granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 we have established dendritic cell (DC) lines from blood mononuclear cells that maintain the antigen capturing and processing capacity characteristic of immature dendritic cells in vivo. These cells have typical dendritic morphology, express high levels of major histocompatibility complex (MHC) class I and class II molecules, CD1, Fc gamma RII, CD40, B7, CD44, and ICAM-1, and lack CD14. Cultured DCs are highly stimulatory in mixed leukocyte reaction (MLR) and are also capable of triggering cord blood naive T cells. Most strikingly, these DCs are as efficient as antigen-specific B cells in presenting tetanus toxoid (TT) to specific T cell clones. Their efficiency of antigen presentation can be further enhanced by specific antibodies via FcR- mediated antigen uptake. Incubation of these cultured DCs with tumor necrosis factor alpha (TNF-alpha) or soluble CD40 ligand (CD40L) for 24 h results in an increased surface expression of MHC class I and class II molecules, B7, and ICAM-1 and in the appearance of the CD44 exon 9 splice variant (CD44-v9); by contrast, Fc gamma RII is markedly and sometimes completely downregulated. The functional consequences of the short contact with TNF-alpha are in increased T cell stimulatory capacity in MLR, but a 10-fold decrease in presentation of soluble TT and a 100-fold decrease in presentation of TT-immunoglobulin G complexes.
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        Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes

         LA Rosén,  G Anhalt,  HJ Rosen (1994)
        Systemic lupus erythematosus is a multisystem autoimmune disease in which the autoantibody response targets a variety of autoantigens of diverse subcellular location. We show here that these autoantigens are clustered in two distinct populations of blebs at the surface of apoptotic cells. The population of smaller blebs contains fragmented endoplasmic reticulum (ER) and ribosomes, as well as the ribonucleoprotein, Ro. The larger blebs (apoptotic bodies) contain nucleosomal DNA, Ro, La, and the small nuclear ribonucleoproteins. These autoantigen clusters have in common their proximity to the ER and nuclear membranes, sites of increased generation of reactive oxygen species in apoptotic cells. Oxidative modification at these sites may be a mechanism that unites this diverse group of molecules together as autoantigens.
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          Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions.

          Culture conditions for human dendritic cells (DC) have been developed by several laboratories. Most of these culture methods, however, have used conditions involving fetal calf serum (FCS) to generate DC in the presence of granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. Recently, alternative culture conditions have been described using an additional stimulation with monocyte-conditioned medium (MCM) and FCS-free media to generate DC. As MCM is a rather undefined cocktail, the yield and quality of DC generated by these cultures varies substantially. We report that a defined cocktail of tumor necrosis factor (TNF)-alpha, IL-1beta and IL-6 equals MCM in its potency to generate DC. Addition of prostaglandin (PG)E2 to the cytokine cocktail further enhanced the yield, maturation, migratory and immunostimulatory capacity of the DC generated. More importantly, culture conditions also influenced the outcome of the T cell response induced. DC cultured with TNF-alpha/IL-1/IL-6 or MCM alone induced CD4+ T cells that release intermediate levels of interferon (IFN)-gamma and no IL-4 or IL-10. Production of IFN-gamma was significantly induced by addition of PGE2, while no effect on production of IL-4 or IL-10 was observed. Even more striking differences were observed for CD8+ T cells. While MCM conditions only induced IFN-gamma(low), IL-4(neg) cells, TNF-alpha/IL-1/IL-6 promoted growth of IFN-gamma(intermediate), IL-4(neg) CD8+ T cells. Addition of PGE2 again only further polarized this pattern enhancing IFN-gamma production by alloreactive CD8+ T cells in both cultures without inducing type 2 cytokines. Taken together, the data indicate that the defined cocktail TNF-alpha/IL-1/IL-6 can substitute for MCM and that addition of PGE2 further enhances the yield and quality of DC generated. TNF-alpha/IL-1, IL-6 + PGE2-cultured DC seem to be optimal for generation of IFN-gamma-producing CD4/CD8+ T cells.
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            Author and article information

            Affiliations
            [ ]Laboratory of Molecular Neuro-oncology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
            [ ]Howard Hughes Medical Institute, Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10065 USA
            [ ]New York Genome Center, 101 Avenue of the Americas, New York, NY 10013 USA
            [ ]Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021 USA
            Contributors
            frankm@rockefeller.edu
            juliak9@gmail.com
            sparveen@rockefeller.edu
            blachen@rockefeller.edu
            dorange@rockefeller.edu
            darnelr@rockefeller.edu
            Journal
            J Transl Med
            J Transl Med
            Journal of Translational Medicine
            BioMed Central (London )
            1479-5876
            5 December 2014
            5 December 2014
            2014
            : 12
            : 1
            25475068 4264264 338 10.1186/s12967-014-0338-3
            © Frank et al.; licensee BioMed Central Ltd. 2014

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Categories
            Research
            Custom metadata
            © The Author(s) 2014

            Medicine

            dendritic cells, vaccine, lymphocytes, immunogenicity, cancer, adjuvant

            Comments

            added an editorial note to Cancer Immunotherapy
            This article was selected by ScienceOpen Consulting Editor, Richard Gallagher, to appear in the Collection entitled Cancer Immunotherapy which can be found here http://ow.ly/Jy1HH. 1. Why this article was chosen: it illustrates the importance of the dendritic cell preparation technique in generating the most potent anti-cancer immune responses possible. 2. What this article shows: Dendritic cells prepared by adherence of peripheral blood mononuclear cells (PBMCs) to plastic were superior to DCs prepared using antibody-conjugated beads in generating anti-tumor activity. The former approach generates a less pure population of dendritic cells, and the presence of activated lymphocytes may contribute to the enhanced response. 3. A key quote from the article: “As we evaluate DC vaccines in the future, it is imperative that we consider methods of DC preparation and how this may play a role in post-vaccination responses.” 4. Corresponding author: Robert Darnell is a Professor in the Laboratory of Molecular Neuro-oncology at Rockefeller University in New York, NY, USA. His laboratory focuses on understanding a group of rare brain diseases, the paraneoplastic neurologic disorders, and how they arise in conjunction with immune responses to cancer.
            2015-02-24 02:55 UTC
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