Oncolytic viruses alter the biogenesis of tumor extracellular vesicles and influence their immunogenicity

Ugo Hirigoyen; Coraly Guilbaud; Morgane Krejbich; Morgane Fouet; Judith Fresquet; Bastien Arnaud; Emmanuelle Com; Charles Pineau; Gwenann Cadiou; Julien Burlaud-Gaillard; Philippe Erbs; Delphine Fradin; Nathalie Labarrière; Jean-François Fonteneau; Tacien Petithomme; Nicolas Boisgerault

doi:10.1016/j.omton.2024.200887

Oncolytic viruses alter the biogenesis of tumor extracellular vesicles and influence their immunogenicity

Mol Ther Oncol. 2024 Sep 26;32(4):200887. doi: 10.1016/j.omton.2024.200887. eCollection 2024 Dec 19.

Authors

Ugo Hirigoyen^{1

2}, Coraly Guilbaud^{1

2}, Morgane Krejbich^{1

2}, Morgane Fouet^{1

2}, Judith Fresquet^{1

2}, Bastien Arnaud^{3

4}, Emmanuelle Com^{3

4}, Charles Pineau^{3

4}, Gwenann Cadiou^{2

5}, Julien Burlaud-Gaillard⁶, Philippe Erbs⁷, Delphine Fradin^{1

2}, Nathalie Labarrière^{2

5}, Jean-François Fonteneau^{1

2}, Tacien Petithomme^{1

2

8}, Nicolas Boisgerault^{1

2}

Affiliations

¹ Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, 44000 Nantes, France.
² LabEx IGO, Nantes Université, 44000 Nantes, France.
³ University Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000 Rennes, France.
⁴ University Rennes, CNRS, Inserm, Biosit UAR 3480 US_S 018, Protim core facility, 35000 Rennes, France.
⁵ Nantes Université, Inserm UMR 1302, CNRS EMR 6001, Université d'Angers, INCIT, 44000 Nantes, France.
⁶ Plate-Forme IBiSA de Microscopie Electronique, Université de Tours and CHRU de Tours, 37000 Tours, France.
⁷ Transgene SA, 67400 Illkirch-Graffenstaden, France.
⁸ Nantes Université, CHU Nantes, 44000 Nantes, France.

Abstract

Extracellular vesicles (EVs) are mediators of intercellular communication in the tumor microenvironment. Tumor EVs are commonly associated with metastasis, immunosuppression or drug resistance. Viral infections usually increase EV secretion, but little is known about the effect of oncolytic viruses (OVs) on tumor EVs. Here, we investigated the impact of oncolytic vesicular stomatitis virus (VSV) and vaccinia virus on EVs secreted by human melanoma and thoracic cancer cells. We found that OV infection increases the production of EVs by tumor cells. These EVs contain proteins of viral origin, such as VSV-G, thus creating a continuum of particles sharing markers of both canonical EVs and viruses. As such, the presence of VSV-G on EVs improves the transfer of their protein content to cell types commonly found in the tumor microenvironment. A proteomic analysis also revealed that EVs-OV secreted during VSV infection are enriched in immunity-related proteins. Finally, CD8⁺ T cells incubated with EVs-OV from infected cells display slightly enhanced cytotoxic functions. Taken together, these data suggest that OVs enhance the communication mediated by tumor EVs, which could participate in the therapeutic efficacy of OVs. These results also provide rationale for engineering OVs to exploit EVs and disseminate therapeutic proteins within the tumor microenvironment.

Keywords: MT: Regular Issue; extracellular vesicles; immunogenicity; immunotherapy; intercellular communication; oncolytic viruses; t cell; vaccinia virus; vesicular stomatitis virus.