EBV-gp350 confers B-cell tropism to tailored exosomes and is a neo-antigen in normal and malignant B cells--a new option for the treatment of B-CLL

• Published in: PloS one Vol. 6; no. 10; p. e25294
• Main Authors: Ruiss, Romana, Jochum, Simon, Mocikat, Ralph, Hammerschmidt, Wolfgang, Zeidler, Reinhard
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-10-2011; Public Library of Science (PLoS)
• Subjects: Adenoviruses; Antigens; Antigens, Viral - immunology; Antiviral agents; B cells; B-Lymphocytes - immunology; B-Lymphocytes - pathology; B-Lymphocytes - virology; Biology; Cancer; CD4-Positive T-Lymphocytes - immunology; CD40 Ligand - metabolism; CD40L protein; Cell culture; Chronic lymphocytic leukemia; Cloning; Cytokines; Cytotoxicity; Epstein-Barr virus; Exosomes; Exosomes - metabolism; Exploitation; Fibroblasts; Flow cytometry; HEK293 Cells; Herpes viruses; Humans; Immune response; Immune response (cell-mediated); Immune system; Immunogenicity; Immunotherapy; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Ligands; Lymphatic leukemia; Lymphocyte Activation - immunology; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine; Otolaryngology; Patients; Peptides; Proteins; T cells; T-Lymphocytes, Cytotoxic - immunology; Tropism; Tropism - immunology; Vaccines; Viral envelope proteins; Viral Matrix Proteins - metabolism; Virus Assembly; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025294

gp350, the major envelope protein of Epstein-Barr-Virus, confers B-cell tropism to the virus by interacting with the B lineage marker CD21. Here we utilize gp350 to generate tailored exosomes with an identical tropism. These exosomes can be used for the targeted co-transfer of functional proteins to normal and malignant human B cells. We demonstrate here the co-transfer of functional CD154 protein on tailored gp350+ exosomes to malignant B blasts from patients with B chronic lymphocytic leukemia (B-CLL), rendering B blasts immunogenic to tumor-reactive autologous T cells. Intriguingly, engulfment of gp350+ exosomes by B-CLL cells and presentation of gp350-derived peptides also re-stimulated EBV-specific T cells and redirected the strong antiviral cellular immune response in patients to leukemic B cells. In essence, we show that gp350 alone confers B-cell tropism to exosomes and that these exosomes can be further engineered to simultaneously trigger virus- and tumor-specific immune responses. The simultaneous exploitation of gp350 as a tropism molecule for tailored exosomes and as a neo-antigen in malignant B cells provides a novel attractive strategy for immunotherapy of B-CLL and other B-cell malignancies.