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Broadening the Message
- Source :
- ACS NANO
- Publication Year :
- 2019
- Publisher :
- American Chemical Society, 2019.
-
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.
- Subjects :
- Lymphoma
CANCER VACCINES
T-Lymphocytes
CLINICAL-APPLICATIONS
TUMOR-CELLS
Cell
Melanoma, Experimental
General Physics and Astronomy
Kaplan-Meier Estimate
02 engineering and technology
Lymphocyte Activation
IMMUNOGENICITY
01 natural sciences
ANERGY INDUCTION
BETA-CATENIN
Mice
Nanoparticle
checkpoint inhibition
Medicine and Health Sciences
Cytotoxic T cell
General Materials Science
alpha-galactosylceramide
Melanoma
Cancer
Immunity, Cellular
Chemistry
nanoparticle
General Engineering
021001 nanoscience & nanotechnology
Natural killer T cell
Killer Cells, Natural
medicine.anatomical_structure
ACTIVATED NKT CELLS
oncology
Female
modified nucleotides
0210 nano-technology
CD1D EXPRESSION
Ovalbumin
T cell
Immunology
Galactosylceramides
Immunopotentiator
010402 general chemistry
Cancer Vaccines
DENDRITIC CELLS
Immune system
Antigen
Antigens, Neoplasm
medicine
Animals
RNA, Messenger
INKT CELLS
Tumor microenvironment
Biology and Life Sciences
0104 chemical sciences
immunothertapy
mRNA vaccine
Liposomes
Cancer research
Natural Killer T-Cells
Subjects
Details
- Language :
- English
- ISSN :
- 19360851 and 1936086X
- Database :
- OpenAIRE
- Journal :
- ACS NANO
- Accession number :
- edsair.doi.dedup.....c4263c2b6ee849b709355749b01ccaf7