Filippo Bellati

Death from metastatic donor-derived ovarian cancer in a male kidney transplant recipient: Letter to the editor

We read with great interest the report on the first case of donor-derived ovarian cancer in a male kidney transplant recipient (1). This report states that the recipient of the second kidney also developed the same disease and suffered the same dismal prognosis. These two cases are of particular interest because, even though both patients suspended immunosuppressive drugs, their immune system and specifically the alloreactive T cells were unable to eradicate the disease.

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Rughetti and colleagues show that unlike soluble glycoprotein antigens, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment, deglycosylates, and generates novel glycoepitopes for presentation by dendritic cells to MUC1-specific CD8+ T cells stimulating IFNγ responses. Tumor-associated glycoproteins are a group of antigens with high immunogenic interest: The glycoforms generated by the aberrant glycosylation are tumor-specific and the novel glycoepitopes exposed can be targets of tumor-specific immune responses. The MUC1 antigen is one of the most relevant tumor-associated glycoproteins. In cancer, MUC1 loses polarity and becomes overexpressed and hypoglycosylated. Changes in glycan moieties contribute to MUC1 immunogenicity and can modify the interactions of tumor cells with antigen-presenting cells such as dendritic cells that would affect the overall antitumor immune response. Here, we show that the form of the MUC1 antigen, i.e., soluble or as microvesicle cargo, influences MUC1 processing in dendritic cells. In fact, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment and is presented by dendritic cells to MUC1-specific CD8+ T cells stimulating IFN-γ responses, whereas the soluble MUC1 is retained in the endolysosomal/HLA-II compartment independently by the glycan moieties and by the modality of internalization (receptor-mediated or non–receptor mediated). MUC1 translocation to the HLA-I compartment is accompanied by deglycosylation that generates novel MUC1 glycoepitopes. Microvesicle-mediated transfer of tumor-associated glycoproteins to dendritic cells may be a relevant biologic mechanism in vivo contributing to define the type of immunogenicity elicited. Furthermore, these results have important implications for the design of glycoprotein-based immunogens for cancer immunotherapy. Cancer Immunol Res; 2(2); 177–86. ©2013 AACR.

Macrophage galactose-type C-type lectin receptor for DC targeting of antitumor glycopeptide vaccines.

e13528 Background: Dendritic cells (DCs) are the most potent antigen presenting cells and are employed in cancer vaccination. Several receptors are being studied in order to identif strategies to increase DCs activating capacity. The C-type lectin macrophage galactose type C-type lectin (MGL), expressed by DCs, is a receptor involved in the recognition of GalNAc (Tn)-carrying antigens. In this study we investigated the possibility of stimulating MGL receptor to increase DC performance by using the MUC1 based glycoimmunogen Tn-MUC1 (MUC19Tn) and the anti-MGL antibody (MLD-1). METHODS DCs were derived from PBMCs of 10 healthy donors and were analyzed before and after MGL engagement using MUC19Tn and MLD-1, as stimulators. DC phenotype, endocytosis, migration and IL-10/IL-12 secretion were evaluated by cytofluorimetry. Allo T cell-stimulating capacity and IFNg and IL-2 T cell production were estimated by 3H-thymidine uptake and ELISpot assay, respectively. DC intracellular signaling and MGL oligomerization were studied by Western Blot and confocal microscopy. RESULTS MGL engagement induces homo-trimers and homo-dimers on DC plasma membrane, promotes the phosphorylation of Erk 1/2 MAP kinases and triggers NFkB classical pathway. The activation of intracellular signals leads to DC phenotypic maturation, with a concomitant reduction of phagocytosis and an enhanced migration capacity (25-30%). After MGL activation, DCs induce a strong proliferation of allogeneic T cells and stimulate high levels of IFNg and IL-2 secretion by both CD8 and CD4 T cells. CONCLUSIONS These results demonstrate that MGL engagement profoundly affects DC plasticity inducing and directing a Th1 immune response. Moreover, MGL receptor expressed on human DC can be targeted by glycopeptide based vaccines with adjuvant activity and tumor specificity.