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Broadening the message : a nanovaccine co-loaded with messenger RNA and α-GalCer induces antitumor immunity through conventional and natural killer T cells

(2019) ACS NANO. 13(2). p.1655-1669
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Abstract
Messenger RNA encoding tumor antigens has the potential to evoke effective antitumor immunity. This study reports on a nanoparticle platform, named mRNA Galsomes, that successfully co-delivers nucleoside-modified antigen-encoding mRNA and the glycolipid antigen and immunopotentiator α-galactosylceramide (α-GC) to antigen-presenting cells after intravenous administration. By co-formulating low doses of α-GC, mRNA Galsomes induce a pluripotent innate and adaptive tumor-specific immune response in mice, with invariant natural killer T cells (iNKT) as a driving force. In comparison, mRNA Galsomes exhibit advantages over the state-of-the-art cancer vaccines using unmodified ovalbumin (OVA)-encoding mRNA, as we observed up to seven times more tumor-infiltrating antigen-specific cytotoxic T cells, combined with a strong iNKT cell and NK cell activation. In addition, the presence of suppressive myeloid cells (myeloid-derived suppressor cells and tumor-associated macrophages) in the tumor microenvironment was significantly lowered. Owing to these antitumor effects, OVA mRNA Galsomes significantly reduced tumor growth in established E.G7-OVA lymphoma, with a complete tumor rejection in 40% of the animals. Moreover, therapeutic vaccination with mRNA Galsomes enhanced the responsiveness to treatment with a PD-L1 checkpoint inhibitor in B16-OVA melanoma, as evidenced by a synergistic reduction of tumor outgrowth and a significantly prolonged median survival. Taken together, these data show that intravenously administered mRNA Galsomes can provide controllable, multifaceted, and effective antitumor immunity, especially when combined with checkpoint inhibition.
Keywords
iNKT cells, T cell, mRNA vaccine, nanoparticle, checkpoint inhibition, alpha-galactosylceramide, modified nucleotides, ACTIVATED NKT CELLS, DENDRITIC CELLS, CLINICAL-APPLICATIONS, ANERGY INDUCTION, CANCER VACCINES, CD1D EXPRESSION, BETA-CATENIN, TUMOR-CELLS, INKT CELLS, IMMUNOGENICITY

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Citation

Please use this url to cite or link to this publication:

Chicago
Verbeke, Rein, Ine Lentacker, Karine Breckpot, Jonas Janssens, Serge Van Calenbergh, Stefaan De Smedt, and Heleen Dewitte. 2019. “Broadening the Message : a Nanovaccine Co-loaded with Messenger RNA and α-GalCer Induces Antitumor Immunity Through Conventional and Natural Killer T Cells.” Acs Nano 13 (2): 1655–1669.
APA
Verbeke, Rein, Lentacker, I., Breckpot, K., Janssens, J., Van Calenbergh, S., De Smedt, S., & Dewitte, H. (2019). Broadening the message : a nanovaccine co-loaded with messenger RNA and α-GalCer induces antitumor immunity through conventional and natural killer T cells. ACS NANO, 13(2), 1655–1669.
Vancouver
1.
Verbeke R, Lentacker I, Breckpot K, Janssens J, Van Calenbergh S, De Smedt S, et al. Broadening the message : a nanovaccine co-loaded with messenger RNA and α-GalCer induces antitumor immunity through conventional and natural killer T cells. ACS NANO. 2019;13(2):1655–69.
MLA
Verbeke, Rein et al. “Broadening the Message : a Nanovaccine Co-loaded with Messenger RNA and α-GalCer Induces Antitumor Immunity Through Conventional and Natural Killer T Cells.” ACS NANO 13.2 (2019): 1655–1669. Print.
@article{8605996,
  abstract     = {Messenger RNA encoding tumor antigens has the potential to evoke effective antitumor immunity. This study reports on a nanoparticle platform, named mRNA Galsomes, that successfully co-delivers nucleoside-modified antigen-encoding mRNA and the glycolipid antigen and immunopotentiator α-galactosylceramide (α-GC) to antigen-presenting cells after intravenous administration. By co-formulating low doses of α-GC, mRNA Galsomes induce a pluripotent innate and adaptive tumor-specific immune response in mice, with invariant natural killer T cells (iNKT) as a driving force. In comparison, mRNA Galsomes exhibit advantages over the state-of-the-art cancer vaccines using unmodified ovalbumin (OVA)-encoding mRNA, as we observed up to seven times more tumor-infiltrating antigen-specific cytotoxic T cells, combined with a strong iNKT cell and NK cell activation. In addition, the presence of suppressive myeloid cells (myeloid-derived suppressor cells and tumor-associated macrophages) in the tumor microenvironment was significantly lowered. Owing to these antitumor effects, OVA mRNA Galsomes significantly reduced tumor growth in established E.G7-OVA lymphoma, with a complete tumor rejection in 40% of the animals. Moreover, therapeutic vaccination with mRNA Galsomes enhanced the responsiveness to treatment with a PD-L1 checkpoint inhibitor in B16-OVA melanoma, as evidenced by a synergistic reduction of tumor outgrowth and a significantly prolonged median survival. Taken together, these data show that intravenously administered mRNA Galsomes can provide controllable, multifaceted, and effective antitumor immunity, especially when combined with checkpoint inhibition.},
  author       = {Verbeke, Rein and Lentacker, Ine and Breckpot, Karine and Janssens, Jonas and Van Calenbergh, Serge and De Smedt, Stefaan and Dewitte, Heleen},
  issn         = {1936-0851},
  journal      = {ACS NANO},
  keywords     = {iNKT cells,T cell,mRNA vaccine,nanoparticle,checkpoint inhibition,alpha-galactosylceramide,modified nucleotides,ACTIVATED NKT CELLS,DENDRITIC CELLS,CLINICAL-APPLICATIONS,ANERGY INDUCTION,CANCER VACCINES,CD1D EXPRESSION,BETA-CATENIN,TUMOR-CELLS,INKT CELLS,IMMUNOGENICITY},
  language     = {eng},
  number       = {2},
  pages        = {1655--1669},
  title        = {Broadening the message : a nanovaccine co-loaded with messenger RNA and α-GalCer induces antitumor immunity through conventional and natural killer T cells},
  url          = {http://dx.doi.org/10.1021/acsnano.8b07660},
  volume       = {13},
  year         = {2019},
}

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