Transfected human dendritic cells to induce antitumor immunity

Rughetti, Aurelia; Biffoni, Mauro; Sabbatucci, Michela; Rahimi, Hassan; Pellicciotta, Ilenia; Fattorossi, Andrea; Pierelli, Luca; Scambia, Giovanni; Lavitrano, Marialuisa; Frati, Luigi; Nuti, Marianna

doi:10.1038/sj.gt.3301266

Cited by 39 publications

(24 citation statements)

References 43 publications

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“…The lipidic formulations lipofectAMINE and lipofectAMINE PLUS (GIBCO-Life Technologies, Paisley, UK) were used to deliver genes into DCs (38). The DNA/lipid compound ratio and the incubation time were selected according to the manufacturer's recommendation.…”

Section: Generation and Transfection Of Dcsmentioning

confidence: 99%

Selective Modification of Antigen-Specific CD4+ T Cells by Retroviral-Mediated Gene Transfer and in Vitro Sensitization with Dendritic Cells

Lin

Wang

2002

Clinical Immunology

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Section: Generation and Transfection Of Dcsmentioning

confidence: 99%

Selective Modification of Antigen-Specific CD4+ T Cells by Retroviral-Mediated Gene Transfer and in Vitro Sensitization with Dendritic Cells

Lin

Wang

2002

Clinical Immunology

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“…Generation of Dendritic Cells (DCs) from PBMC (PBMCs) was performed as described previously (21). In brief, PBMC were isolated by FicollHypaque (1.077 g/ml, Pharmacia, LKB, Sweden) density gradient centrifugation of anti-coagulated blood obtained from buffy coat preparations of healthy volunteers from the Blood Bank, University of Rome "La Sapienza."…”

Section: Generation and Culture Of Dcsmentioning

confidence: 99%

Recombinant Tumor-Associated MUC1 Glycoprotein Impairs the Differentiation and Function of Dendritic Cells

Rughetti

Pellicciotta

Biffoni

et al. 2005

The Journal of Immunology

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Tumors exploit several strategies to evade immune recognition, including the production of a large number of immunosuppressive factors, which leads to reduced numbers and impaired functions of dendritic cells (DCs) in the vicinity of tumors. We have investigated whether a mucin released by tumor cells could be involved in causing these immunomodulating effects on DCs. We used a recombinant purified form of the MUC1 glycoprotein, an epithelial associated mucin that is overexpressed, aberrantly glycosylated, and shed during cancer transformation. The O-glycosylation profile of the recombinant MUC1 glycoprotein (ST-MUC1) resembled that expressed by epithelial tumors in vivo, consisting of large numbers of sialylated core 1 (sialyl-T, ST) oligosaccharides. When cultured in the presence of ST-MUC1, human monocyte-derived DCs displayed a modified phenotype with decreased expression of costimulatory molecules (CD86, CD40), Ag-presenting molecules (DR and CD1d), and differentiation markers (CD83). In contrast, markers associated with an immature phenotype, CD1a and CD206 (mannose receptor), were increased. This effect was already evident at day 4 of DC culture and was dose dependent. The modified phenotype of DCs corresponded to an altered balance in IL-12/IL-10 cytokine production, with DC expressing an IL-10highIL-12low phenotype after exposure to ST-MUC1. These DCs were defective in their ability to induce immune responses in both allogeneic and autologous settings, as detected in proliferation and ELISPOT assays. The altered DC differentiation and Ag presentation function induced by the soluble sialylated tumor-associated mucin may represent a mechanism by which epithelial tumors can escape immunosurveillance.

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“…Similarly to the transfection of tumour cells with polynucleotides coding for TAAs or immune stimulatory cytokines, and transduction of tumours in vivo with immune stimulatory viruses (for a review, see Schirrmacher et al 1998Schirrmacher et al , 2000, DCs were transfected either with polynucleotides, DNA or RNA, coding for TAAs, or with DNA encoding immunostimulatory cytokines and costimulatory molecules. The delivery of genes coding for antigenic epitopes or other molecules with a recombinant retrovirus, adenovirus, or poxvirus into dendritic cells has also been used for transduction and therapy (Boczkowski et al 1996(Boczkowski et al , 2000Bubenik 1999;Condon et al 1996;Henderson et al 1996;Ishida et al 1999;Jenne et al 2000;Kin et al 1997;PeÂ rez-Diez et al 1998;Reeves et al 1996;Rughetti et al 2000;Specht et al 1997;Van Tendeloo et al 1998;Want et al 2000;Yang et al 1999). It has been reported that transfection and activation of DCs plays a key role also during conventional DNA vaccination (Akbari et al 1999).…”

mentioning

confidence: 97%

Utilization of oncoprotein-pulsed dendritic cells as tumor vaccines

Bubenı́k

2001

J Cancer Res Clin Oncol

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Dendritic cells (DCs) are the most potent professional antigen-presenting cells with exquisite capacity to interact with T cells and initiate their responses. They specialize in capturing and processing antigens to form MHC peptide complexes (BubenõÂ k 1996). Two key functions of DCs segregate over time. First, the immature DCs, which are found in most of the non-lymphoid and all lymphoid tissues of the body, internalize the antigen. Then, a day or more later, they express the processed antigen in the context of MHC molecules on the cell surface and stimulate T cells. The CD8 + T cells are stimulated in the context of MHC class I molecules, whereas the CD4 + T cells are stimulated in the context of MHC class II molecules (Banchereau and Steinman 1998). Both the CD4 + helper T cells and the CD8 + cytotoxic T lymphocyte precursors must recognize antigen on the same DC (Keene and Forman 1982;Bennett et al. 1997). This ®nding led to the view that help for CD8 + T cell responses is mediated via soluble, shortrange (BubenõÂ k et al. 2000) cytokine signals such as interleukin-2 which are secreted by activated CD4 + T cells. In other words, the DC is required to facilitate delivery of short-range cytokines secreted by the CD4 + helper T cells to the antigen-speci®c CD8 + T cells by bringing the appropriate antigen-speci®c CD4 + and CD8 + T cells together (Clarke 2000). Alternatively, the CD4 + T help is delivered indirectly, through activation and conversion of the DC into a stimulatory cell for CD8 + T lymphocyte priming (Guerder and Matzinger 1992). It has been shown that CD4 + T cell help for CD8 + T cell priming occurs through CD40-CD40L interaction. After recognition of antigen expressed on the surface of DCs, CD40L is rapidly upregulated on CD4 + T cells. Signaling through CD40 on DCs can increase the expression of costimulatory and adhesion molecules such as CD80, CD86, CD23, CD58, and CD54, as well as upregulating class I and class II MHC expression on DCs, which are the events required for cytotoxic T lymphocyte responses (Caux et alMoreover, CD40 signaling may replace the requirement for CD4 + T cell help in cytotoxic T lymphocyte responses. The reports by Bennett et al. (1998) and Schoenberger et al. (1998) indicate that signaling through CD40 on DCs mediated by anti-CD40-stimulating antibody can induce CD8 + T cell priming in the absence of CD4 + T helper cells, thereby weakening the ®rst alternative, i.e., the view that help is delivered through CD4 + T cell-secreted cytokines.The unique antigen-presenting capabilities of DCs make them attractive vehicles for the delivery of therapeutic cancer vaccines. The working hypothesis for utilization of DC-based cancer vaccines is that lack of tumor antigen presentation on mature, stimulatory DCs in vivo, which is a major problem in tumor-bearing individuals, can be bypassed by direct loading of DCs with oncoproteins in vitro, ensuring the transfer of the immunodominant peptides on the adequate antigen-presenting molecules (Schuler and Steinman 1997). Indirect eviden...

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Transfected human dendritic cells to induce antitumor immunity

Cited by 39 publications

References 43 publications

Selective Modification of Antigen-Specific CD4+ T Cells by Retroviral-Mediated Gene Transfer and in Vitro Sensitization with Dendritic Cells

Selective Modification of Antigen-Specific CD4+ T Cells by Retroviral-Mediated Gene Transfer and in Vitro Sensitization with Dendritic Cells

Recombinant Tumor-Associated MUC1 Glycoprotein Impairs the Differentiation and Function of Dendritic Cells

Utilization of oncoprotein-pulsed dendritic cells as tumor vaccines

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