TY - JOUR
T1 - Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity
AU - Hamouda, Ahmed E. I.
AU - Filtjens, Jessica
AU - Brabants, Elisabeth
AU - Kancheva, Daliya
AU - Debraekeleer, Ayla
AU - Brughmans, Jan
AU - Jacobs, Lotte
AU - Bardet, Pauline M. R.
AU - Knetemann, Elisabeth
AU - Lefesvre, Pierre
AU - Allonsius, Lize
AU - Gontsarik, Mark
AU - Varela, Ismael
AU - Crabbé, Marian
AU - Clappaert, Emile J.
AU - Cappellesso, Federica
AU - Caro, Aarushi A.
AU - Peiró, Alícia Gordún
AU - Fredericq, Luna
AU - Hadadi, Eva
AU - Senti, Mariona Estapé
AU - Schiffelers, Raymond
AU - Grunsven, Leo A. van
AU - Nana, Frank Aboubakar
AU - Geest, Bruno G. De
AU - Deschoemaeker, Sofie
AU - Koker, Stefaan De
AU - Lambolez, Florence
AU - Laoui, Damya
N1 - Funding Information:
We thank Nadia Abou, Constantinos Papadopoulos, Eleonora Omasta, Ellen Vaneetvelde, and Mait\u00E9 Schuurmans for administrative and technical assistance. We are thankful to the VIB single cell core for providing access to RNA sequencing technologies and the Flow Cytometry Core Facility of Vrije Universiteit Brussel for the use of the Symphony A3 Flow Cytometer. A.E.I.H., J.F., E.B., A.D., L.J., I.V., M.C., S.D.K. and F.L. are supported by a grant from VLAIO (Flanders innovation & entrepreneurship (HBC.2019.2737). J.F., E.B., L.J., I.V., M.C., M.E.S., R.S., S.D.K. and F.L. were supported by the EXPERT project, which has received Funding from the European Union\u2019s Horizon 2020 research and innovation program under Grant Agreement No. 825828. P.M.R.B, L.A., A.A.C. and A.G.P. are supported by predoctoral grants from FWO Vlaanderen (1154720\u2009N, 11P1824N, 1169521\u2009N, 1SH0424N). E.K and LAvG are funded by grants from the FWO and Vrije Universiteit Brussel. M.G. and B.G.D.G. are supported by grants from Stichting tegen kanker and Ghent University. F.C and L.F are supported by Vrije Universiteit Brussel. E.H. is supported by a postdoctoral grant from FWO Vlaanderen (12Y1922N). F.A.N is supported by the Fonds de la Recherche Scientifique FNRS (Belgium) Grants and Fellowships, S.D.S is supported by a postdoctoral grant from Stichting tegen kanker (2021-023). D.L. is supported by grants from FWO, Kom op tegen Kanker, Stichting tegen kanker, VIB and Vrije Universiteit Brussel.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12/6
Y1 - 2024/12/6
N2 - Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.
AB - Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.
UR - https://doi.org/10.1038/s41467-024-54877-9
UR - http://www.scopus.com/inward/record.url?scp=85211387402&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-54877-9
DO - 10.1038/s41467-024-54877-9
M3 - Article
C2 - 39639025
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 10635
ER -