title: HPV-E7 delivered by engineered exosomes elicits a protective CD8⁺ T cell-mediated immune response.
abstract: We developed an innovative strategy to induce a cytotoxic T cell (CTL) immune response against protein antigens of choice. It relies on the production of exosomes, i.e., nanovesicles spontaneously released by all cell types. We engineered the upload of huge amounts of protein antigens upon fusion with an anchoring protein (i.e., HIV-1 Nefmut), which is an inactive protein incorporating in exosomes at high levels also when fused with foreign proteins. We compared the immunogenicity of engineered exosomes uploading human papillomavirus (HPV)-E7 with that of lentiviral virus-like particles (VLPs) incorporating equivalent amounts of the same antigen. These exosomes, whose limiting membrane was decorated with VSV-G, i.e., an envelope protein inducing pH-dependent endosomal fusion, proved to be as immunogenic as the cognate VLPs. It is noteworthy that the immunogenicity of the engineered exosomes remained unaltered in the absence of VSV-G. Most important, we provide evidence that the inoculation in mouse of exosomes uploading HPV-E7 induces production of anti-HPV E7 CTLs, blocks the growth of syngeneic tumor cells inoculated after immunization, and controls the development of tumor cells inoculated before the exosome challenge. These results represent the proof-of-concept about both feasibility and efficacy of the Nefmut-based exosome platform for the induction of CD8+ T cell immunity.
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy. paola.dibonito@iss.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Bonito
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy. barbara.ridolfi@iss.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ridolfi
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy. sandra.columbacabezas@iss.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Columba-Cabezas
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy. andrea.giovannelli@iss.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giovannelli
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, 00161 Rome, Italy. chiara.chiozzini@iss.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Chiozzini
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, 00161 Rome, Italy. francesco.manfredi@iss.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Manfredi
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, 00161 Rome, Italy. simona.anticoli@iss.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Anticoli
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, 00161 Rome, Italy. claudia.arenaccio@guest.iss.it.|Department of Science, University Roma Tre, 00146 Rome, Italy. claudia.arenaccio@guest.iss.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Arenaccio
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, 00161 Rome, Italy. maurizio.federico@iss.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Federico
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004337:Drug Carriers / Q000008:administration & dosage*; D055354:Exosomes / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000008:administration & dosage / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D004337:Drug Carriers; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines