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.
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.
Department of Gene Vectors, Helmholtz-Zentrum, Munich, Germany.
Romana
R
Ruiss
Simon
S
Jochum
Ralph
R
Mocikat
Wolfgang
W
Hammerschmidt
Reinhard
R
Zeidler
D000956:Antigens, Viral / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018523:Tropism / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D019065:Virus Assembly
D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D023201:CD40 Ligand