Lymph Node Macrophages Drive Innate Immune Responses to Enhance the Anti-tumor Efficacy of MRNA Vaccines

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2024 Jan 20

PMID 38243602

Authors

Kenji Kubara

Kazuto Yamazaki

Takayuki Miyazaki

Keita Kondo

Daisuke Kurotaki

Tomohiko Tamura

Yuta Suzuki

Affiliations

Soon will be listed here.

Abstract

mRNA vaccines are promising for cancer treatment. Efficient delivery of mRNAs encoding tumor antigens to antigen-presenting cells (APCs) is critical to elicit anti-tumor immunity. Herein, we identified a novel lipid nanoparticle (LNP) formulation, L17-F05, for mRNA vaccines by screening 34 ionizable lipids and 28 LNP formulations using human primary APCs. Subcutaneous delivery of L17-F05 mRNA vaccine encoding Gp100 and Trp2 inhibited tumor growth and prolonged the survival of mice bearing B16F10 melanoma. L17-F05 efficiently delivered mRNAs to conventional dendritic cells (cDCs) and macrophages in draining lymph nodes (dLNs). cDCs functioned as the main APCs by presenting antigens along with enhanced expression of co-stimulatory molecules. Macrophages triggered innate immune responses centered on type-I interferon (IFN-I) in dLNs. Lymph node (LN) macrophage depletion attenuated APC maturation and anti-tumor activity of L17-F05 mRNA vaccines. Loss-of-function studies revealed that L17-F05 works as a self-adjuvant by activating the stimulator of interferon genes (STING) pathway in macrophages. Collectively, the self-adjuvanticity of L17-F05 triggered innate immune responses in LN macrophages via the STING-IFN-I pathway, contributing to APC maturation and potent anti-tumor activity of L17-F05 mRNA vaccines. Our findings provide strategies for further optimization of mRNA vaccines based on the innate immune response driven by LN macrophages.

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References

Tahtinen S, Tong A, Himmels P, Oh J, Paler-Martinez A, Kim L . IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat Immunol. 2022; 23(4):532-542. DOI: 10.1038/s41590-022-01160-y. View

Chatziandreou N, Farsakoglu Y, Palomino-Segura M, DAntuono R, Pizzagalli D, Sallusto F . Macrophage Death following Influenza Vaccination Initiates the Inflammatory Response that Promotes Dendritic Cell Function in the Draining Lymph Node. Cell Rep. 2017; 18(10):2427-2440. DOI: 10.1016/j.celrep.2017.02.026. View

Kranz L, Diken M, Haas H, Kreiter S, Loquai C, Reuter K . Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016; 534(7607):396-401. DOI: 10.1038/nature18300. View

Jayaraman M, Ansell S, Mui B, Tam Y, Chen J, Du X . Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed Engl. 2012; 51(34):8529-33. PMC: 3470698. DOI: 10.1002/anie.201203263. View

Lederer K, Castano D, Gomez Atria D, Oguin 3rd T, Wang S, Manzoni T . SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation. Immunity. 2020; 53(6):1281-1295.e5. PMC: 7680029. DOI: 10.1016/j.immuni.2020.11.009. View

Suzuki Y, Hyodo K, Suzuki T, Tanaka Y, Kikuchi H, Ishihara H . Biodegradable lipid nanoparticles induce a prolonged RNA interference-mediated protein knockdown and show rapid hepatic clearance in mice and nonhuman primates. Int J Pharm. 2017; 519(1-2):34-43. DOI: 10.1016/j.ijpharm.2017.01.016. View

Groom J, Luster A . CXCR3 in T cell function. Exp Cell Res. 2011; 317(5):620-31. PMC: 3065205. DOI: 10.1016/j.yexcr.2010.12.017. View

Mueller D, Jenkins M, Schwartz R . Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989; 7:445-80. DOI: 10.1146/annurev.iy.07.040189.002305. View

Moseman E, Iannacone M, Bosurgi L, Tonti E, Chevrier N, Tumanov A . B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. Immunity. 2012; 36(3):415-26. PMC: 3359130. DOI: 10.1016/j.immuni.2012.01.013. View

10.

Conrady C, Zheng M, Mandal N, van Rooijen N, Carr D . IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice. Mucosal Immunol. 2012; 6(1):45-55. PMC: 3449026. DOI: 10.1038/mi.2012.46. View

11.

Suzuki Y, Miyazaki T, Muto H, Kubara K, Mukai Y, Watari R . Design and lyophilization of lipid nanoparticles for mRNA vaccine and its robust immune response in mice and nonhuman primates. Mol Ther Nucleic Acids. 2022; 30:226-240. PMC: 9508692. DOI: 10.1016/j.omtn.2022.09.017. View

12.

Li B, Luo X, Deng B, Wang J, McComb D, Shi Y . An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo. Nano Lett. 2015; 15(12):8099-107. PMC: 4869688. DOI: 10.1021/acs.nanolett.5b03528. View

13.

Hassett K, Benenato K, Jacquinet E, Lee A, Woods A, Yuzhakov O . Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines. Mol Ther Nucleic Acids. 2019; 15:1-11. PMC: 6383180. DOI: 10.1016/j.omtn.2019.01.013. View

14.

Hashiba A, Toyooka M, Sato Y, Maeki M, Tokeshi M, Harashima H . The use of design of experiments with multiple responses to determine optimal formulations for in vivo hepatic mRNA delivery. J Control Release. 2020; 327:467-476. DOI: 10.1016/j.jconrel.2020.08.031. View

15.

Chen L, Flies D . Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013; 13(4):227-42. PMC: 3786574. DOI: 10.1038/nri3405. View

16.

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

17.

Da Silva Sanchez A, Zhao K, Huayamares S, Hatit M, Lokugamage M, Loughrey D . Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery. J Control Release. 2022; 353:270-277. PMC: 9897220. DOI: 10.1016/j.jconrel.2022.11.037. View

18.

Suzuki Y, Ishihara H . Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs. Drug Metab Pharmacokinet. 2021; 41:100424. PMC: 8502116. DOI: 10.1016/j.dmpk.2021.100424. View

19.

Kawase W, Kurotaki D, Suzuki Y, Ishihara H, Ban T, Sato G . siRNA-loaded biodegradable lipid nanoparticles ameliorate concanavalin A-induced liver injury. Mol Ther Nucleic Acids. 2021; 25:708-715. PMC: 8463440. DOI: 10.1016/j.omtn.2021.08.023. View

20.

LoPresti S, Arral M, Chaudhary N, Whitehead K . The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs. J Control Release. 2022; 345:819-831. PMC: 9447088. DOI: 10.1016/j.jconrel.2022.03.046. View