Guevara Maria L, Jilesen Zachary, Stojdl David, Persano Stefano
Children's Hospital of Eastern Ontario (CHEO) Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1N 6N5, Canada.
Istituto Italiano di Tecnologia (IIT), Via Morego 30, Genova 16163, Italy.
ACS Omega. 2019 Aug 7;4(8):13015-13026. doi: 10.1021/acsomega.9b00489. eCollection 2019 Aug 20.
Recently, the use of mRNA-based vaccines for cancer immunotherapy has gained growing attention. Several studies have shown that mRNA delivered in a vectorized format can generate a robust and efficient immune response. In this work, a new lipopolyplex vector (multi-LP), incorporating the immune adjuvant α-galactosylceramide (α-GalCer) and a multivalent cationic lipid, was proposed for the in vivo delivery of mRNA into antigen-presenting cells. We demonstrate that dendritic cells (DCs) can be targeted in vivo by intravenous administration of a α-GalCer-/mRNA-loaded multi-LP vector, without the need for its functionalization with cell-specific antibodies or ligands. The multi-LP nanoparticles loaded with a reporter mRNA efficiently led to high expression of the enhanced green fluorescence protein in DCs both in vitro and in vivo, exhibiting an intrinsic selectivity for DCs. Finally, the TRP2-mRNA/α-GalCer-based multi-LP vaccine induced a significant therapeutic effect against a highly malignant B16-F10 melanoma tumor. This study provides the first evidence that a combination of antigen-mRNA and α-GalCer can be used as an effective antitumor vaccine, inducing strong innate and adaptive immune responses.
最近，基于mRNA的癌症免疫疗法的应用受到越来越多的关注。多项研究表明，以载体形式递送的mRNA能够产生强大而有效的免疫反应。在这项工作中，一种新的脂质多聚体载体（multi-LP）被提出用于将mRNA体内递送至抗原呈递细胞，该载体包含免疫佐剂α-半乳糖神经酰胺（α-GalCer）和一种多价阳离子脂质。我们证明，通过静脉注射负载α-GalCer和mRNA的multi-LP载体可在体内靶向树突状细胞（DC），而无需用细胞特异性抗体或配体对其进行功能化修饰。负载报告基因mRNA的multi-LP纳米颗粒在体外和体内均能有效地使DC中增强型绿色荧光蛋白高表达，显示出对DC的内在选择性。最后，基于TRP2-mRNA/α-GalCer的multi-LP疫苗对高度恶性的B16-F10黑色素瘤肿瘤产生了显著的治疗效果。这项研究首次证明，抗原mRNA与α-GalCer的组合可作为一种有效的抗肿瘤疫苗，诱导强烈的先天性和适应性免疫反应。
