Local administration of mRNA encoding cytokine cocktail confers potent anti-tumor immunity

作者：Zhigang Li, Ling Hu, Yiping Wang, Qi Liu, Jun Liu, Haiyan Long, Qi Li, Liping Luo, Yucai Peng · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2024.1455019 · 被引用次数：16 · 研究领域：Immunotherapy and Immune Responses、CAR-T cell therapy research、RNA Interference and Gene Delivery

Immunotherapy using inflammatory cytokines, such as interleukin (IL)-2 and interferon (IFN)-α, has been clinically validated in treating various cancers. However, systemic immunocytokine-based therapies are limited by the short half-life of recombinant proteins and severe dose-limiting toxicities. In this study, we exploited local immunotherapy by intratumoral administration of lipid nanoparticle (LNP)-encapsulated mRNA cocktail encoding cytokines IL-12, IL-7, and IFN-α. The cytokine mRNA cocktail induced tumor regression in multiple syngeneic mouse models and anti-tumor immune memory in one syngeneic mouse model. Additionally, immune checkpoint blockade further enhanced the anti-tumor efficacy of the cytokine mRNAs. Furthermore, human cytokine mRNAs exhibited robust anti-tumor efficacy in humanized mouse tumor models. Mechanistically, cytokine mRNAs induced tumor microenvironment inflammation, characterized by robust T cell infiltration and significant inflammatory cytokine and chemokine production.