Publications by authors named "Corlien A Aarnoudse"

7 Publications

  • Page 1 of 1

Glycan modification of the tumor antigen gp100 targets DC-SIGN to enhance dendritic cell induced antigen presentation to T cells.

Int J Cancer 2008 Feb;122(4):839-46

Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands.

Dendritic cells (DC) have gained much interest in the field of anticancer vaccine development because of their central function in immune regulation. However, the clinical application of ex vivo cultured DC has significant disadvantages. A vaccine that targets dendritic cells in vivo and enhances antigen presentation would be of great benefit. Because of its DC-restricted expression pattern, and its function as an antigen uptake receptor, DC-SIGN is an interesting candidate target structure for human immature DC. Here, we studied whether modification of the melanoma differentiation antigen gp100 with DC-SIGN-interacting glycans enhances targeting to human DC. A high-mannose form of gp100, as protein or as tumor lysate, not only interacted specifically with DC through DC-SIGN but also resulted in an enhanced antigen presentation to gp100-specific CD4(+) T cells. Our results indicate that glycan modification of tumor antigens to target C-type lectin receptors, such as DC-SIGN, is a new way to develop in vivo targeting DC strategies that simultaneously enhance the induction of tumor-specific T cells.
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http://dx.doi.org/10.1002/ijc.23101DOI Listing
February 2008

MGL-mediated internalization and antigen presentation by dendritic cells: a role for tyrosine-5.

Eur J Immunol 2007 Aug;37(8):2075-81

Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands.

Professional antigen-presenting cells are essential for the initiation of adaptive immune responses; however, they also play a vital role in the maintenance of tolerance towards self-antigens. C-type lectins can function as antigen receptors by capturing carbohydrate ligands for processing and presentation. Here, we focused on the dendritic cell (DC)-expressed macrophage galactose-type lectin (MGL), a C-type lectin with a unique specificity for terminal GalNAc residues, such as the tumor-associated Tn antigen. Soluble model antigens are efficiently internalized by MGL and subsequently presented to responder CD4+ T cells. The tyrosine-5 residue in the YENF motif, present in the MGL cytoplasmic domain, was essential for the MGL-mediated endocytosis in CHO cells. In conclusion, MGL contributes to the antigen processing and presentation capacities of DC and may provide a suitable target for the initiation of anti-tumor immune responses.
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http://dx.doi.org/10.1002/eji.200636838DOI Listing
August 2007

Recognition of tumor glycans by antigen-presenting cells.

Curr Opin Immunol 2006 Feb 21;18(1):105-11. Epub 2005 Nov 21.

Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center Amsterdam, PO Box 7057, 1081 BT Amsterdam, The Netherlands.

C-type lectin receptors on antigen-presenting cells are potent antigen-uptake receptors with specificity for glycan structures. Glycosylation changes during malignant transformation create tumor-specific carbohydrate structures that interact with C-type lectins on dendritic cells. Recent findings revealed that tumor glycoproteins, such as carcinoembryonic antigen and MUC-1, indeed interact with the C-type lectins DC-SIGN and macrophage galactose-type lectin on antigen-presenting cells. The consequences for anti-cancer immunity or tolerance induction can be extrapolated from the function of C-type lectins in pathogen recognition and antigen presentation. In addition, in vivo studies in mice recently demonstrated the potency of targeting antigens to C-type lectins on antigen-presenting cells for anti-tumor vaccination strategies.
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http://dx.doi.org/10.1016/j.coi.2005.11.001DOI Listing
February 2006

Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin.

Cancer Res 2005 Jul;65(13):5935-44

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.

Dendritic cells play a pivotal role in the induction of antitumor immune responses. Immature dendritic cells are located intratumorally within colorectal cancer and intimately interact with tumor cells, whereas mature dendritic cells are present peripheral to the tumor. The majority of colorectal cancers overexpress carcinoembryonic antigen (CEA), and malignant transformation changes the glycosylation of CEA on colon epithelial cells, resulting in higher levels of Lewis(x) and de novo expression of Lewis(y) on tumor-associated CEA. Dendritic cells express the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) that has high affinity for nonsialylated Lewis antigens, so we hypothesized that DC-SIGN is involved in recognition of colorectal cancer cells by dendritic cells. We show that immature dendritic cells within colorectal cancer express DC-SIGN and that immature dendritic cells but not mature dendritic cells interact with tumor cells. DC-SIGN mediates these interactions through binding of Lewis(x) and Lewis(y) carbohydrates on CEA of colorectal cancer cells. In contrast, DC-SIGN does not bind CEA expressed on normal colon epithelium that contains low levels of Lewis antigens. This indicates that dendritic cells may recognize colorectal cancer cells through binding of DC-SIGN to tumor-specific glycosylation on CEA. Similar to pathogens that target DC-SIGN to escape immunosurveillance, tumor cells may interact with DC-SIGN to suppress dendritic cell functions.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-4140DOI Listing
July 2005

Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells.

Int Immunol 2005 May 31;17(5):661-9. Epub 2005 Mar 31.

Department of Molecular Cell Biology & Immunology, VU Medical Center, Amsterdam, The Netherlands.

Dendritic cells (DCs) are key to the maintenance of peripheral tolerance to self-antigens and the orchestration of an immune reaction to foreign antigens. C-type lectins, expressed by DCs, recognize carbohydrate moieties on antigens that can be internalized for processing and presentation. Little is known about the exact glycan structures on self-antigens and pathogens that are specifically recognized by the different C-type lectins and how this interaction influences DC function. We have analyzed the carbohydrate specificity of the human C-type lectin macrophage galactose-type lectin (MGL) using glycan microarray profiling and identified an exclusive specificity for terminal alpha- and beta-linked GalNAc residues that naturally occur as parts of glycoproteins or glycosphingolipids. Specific glycan structures containing terminal GalNAc moieties, expressed by the human helminth parasite Schistosoma mansoni as well as tumor antigens and a subset of gangliosides, were identified as ligands for MGL. Our results indicate an endogenous function for DC-expressed MGL in the clearance and tolerance to self-gangliosides, and in the pattern recognition of tumor antigens and foreign glycoproteins derived from helminth parasites.
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http://dx.doi.org/10.1093/intimm/dxh246DOI Listing
May 2005

CD4+ Th2 cell recognition of HLA-DR-restricted epitopes derived from CAMEL: a tumor antigen translated in an alternative open reading frame.

J Immunol 2003 Feb;170(3):1490-7

Department of Clinical Oncology, Leiden University Medical Center, The Netherlands.

Tumor Ag NY-ESO-1 is an attractive target for immunotherapy of cancer, since both CD8(+) CTL and CD4(+) Th cells against NY-ESO-1 have been described. Moreover, NY-ESO-1 as well as the highly homologous tumor Ag LAGE-1 are broadly expressed in various tumor types. Interestingly, the NY-ESO-1 and LAGE-1 genes also encode for proteins translated in an alternative open reading frame. These alternatively translated NY-ESO-ORF2 and CAMEL proteins, derived from the NY-ESO-1 and LAGE-1 genes, respectively, have been demonstrated to be immunogenic, since CTL specific for these proteins have been isolated from melanoma patients. In this study a panel of advanced melanoma patients was screened for the presence of Th cells specific for the alternatively translated tumor Ags NY-ESO-ORF2 and CAMEL. PBMC of melanoma patients were stimulated for 4 days with mixes of overlapping peptides covering the entire NY-ESO-ORF2 and CAMEL protein sequences and were tested for the release of type 1 (IFN-gamma) and type 2 (IL-13) cytokines in ELISPOT assays. In three of 15 patients, T cells specific for two CAMEL peptides (CAMEL(71-92) and CAMEL(81-102)) could be detected. From one of these patients, CD4(+) T cell clones specific for CAMEL(81-102) could be generated. These clones recognized a naturally processed epitope presented in both HLA-DR11 and HLA-DR12 and produced high levels of IL-4, IL-5, and IL-13. In conclusion, this study shows the presence of Th cells specific for the alternatively translated tumor Ag CAMEL in melanoma patients and is the first report that describes the isolation of tumor Ag-specific CD4(+) Th 2 clones.
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http://dx.doi.org/10.4049/jimmunol.170.3.1490DOI Listing
February 2003

TCR reconstitution in Jurkat reporter cells facilitates the identification of novel tumor antigens by cDNA expression cloning.

Int J Cancer 2002 May;99(1):7-13

Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.

The identification of novel tumor antigens is of extreme importance for effective immunotherapy against cancer. A major obstacle in this field is the limited life span of tumor-specific cytotoxic T lymphocytes (CTLs) in vitro. Therefore we searched for a method to isolate the tumor specificity of these CTLs, i.e., their T-cell receptors (TCRs) and transfer it to an immortalized T-cell line. For this purpose, a TCR-negative Jurkat T-cell line was equipped with a nuclear factor of activated T cells (NFAT)-luciferase reporter construct to allow measurement of TCR-mediated activation. To establish the feasibility of this tumor-specific TCR transduction, we cloned the TCR genes of a known T-cell clone specific for the tumor antigen CAMEL (CTL-recognized antigen on melanoma) into a retroviral construct. Jurkat reporter cells transduced with this construct, Jrt-TCRalpha3beta5, were tested for their reactivity against CAMEL-expressing melanoma cells, peptide-loaded T2 cells and CAMEL-transfected COS-1 cells. The melanoma cell lines were poorly recognized, but peptide-pulsed and -transfected cells effectively stimulated NFAT signaling. The activation of TCR(+) Jurkat reporter cells was shown to be dependent on the antigen density on the target cells and the expression level of the coreceptor CD8 on the Jurkat cells. To verify the benefit of this TCR reconstitution method for identification of novel antigens, pools of the cDNA library from which CAMEL was originally cloned were transfected in COS-1 cells and screened with Jrt-TCRalpha3beta5. Identical cDNA pools were found that were positive with these cells and with the CAMEL-specific CTL clone. Our results illustrate that TCR-reconstituted Jurkat reporter cells are a useful tool in the identification of novel tumor antigens by cDNA expression cloning.
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http://dx.doi.org/10.1002/ijc.10317DOI Listing
May 2002
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