Second generation of LNP based mRNA vaccine leads to a T cell–inflamed tumor microenvironment favorable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumor model

免疫系统 肿瘤微环境 癌症免疫疗法 CD8型 趋化因子 癌症研究 佐剂 T细胞 获得性免疫系统 抗原 免疫疗法 CXCL10型 树突状细胞 生物 免疫学
作者
Carole Fournier,Marion Mercey-Ressejac,Valentin Dérangère,Amal Al Kadi,David Rageot,Christine Charrat,Alexis Leroy,Marie Escudé,Séverine Escaich,François Ghiringhelli,Thomas Decaens,Fabrice Navarro,Evelyne Jouvin‐Marche,Patrice N. Marche
出处
期刊: [Cold Spring Harbor Laboratory]
被引量:1
标识
DOI:10.1101/2024.07.24.604918
摘要

Abstract The delivery of mRNA-based cancer vaccines has demonstrated significant promise in triggering antitumor immune responses. With the aim of using them in combination with other immunotherapies already used in the clinical appropriately, the modifications of the intratumoral immune microenvironment needs to be deeply characterized. We have shown that the second generation of lipid nanoparticles (LNPs), nanostructured lipid carriers (so-called Lipidots ® ), are able to vector protein antigens and nucleic acids. Here, we test Lipidots ® for the delivery of mRNA encoding OVA antigen and eliciting a specific antitumor immune response. We demonstrate in vitro that our LNPs deliver mRNA into dendritic cells (DCs), when complexed with mRNA, activate DCs through the TLR4/8 and ROS signaling pathways and induce specific CD4 + and CD8 + T cell activation. Our vaccinal strategy exhibits significant antitumor efficacy both in the context of tumor prevention and as a therapeutic vaccine in B16OVA and E.G7-OVA cold tumors. The LNP-Ova mRNA vaccine induces a profound intratumoral remodeling of the innate and adaptive immunity associated with an increase in the gene expression of chemokines ( Cxcl10, Cxcl11, Cxcl9 ) involved in CD8 + T cell attraction. Additionally, the vaccine induces the establishment of an escape mechanism mediated by PD-1/PDL-1 axis, making it an adjuvant therapy for optimized responses to the blocking of this signaling pathway. Finally, the combination of vaccine and anti-PD-1 therapy achieves a much higher rate of complete responses and memory immune responses compared to monotherapies. Our work demonstrates the capability of Lipidots ® as an effective platform for the development of preventive and therapeutic vaccines against cancer based on mRNA delivery and that combination with other immunotherapies such as immune checkpoint blockers could counter tumor resistance and promote long-term antitumor immunity.

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