PDF(Pubmed)
Abstract：
An mRNA with unmodified nucleosides induces type I interferons (IFN-I) through the stimulation of innate immune sensors. Whether IFN-I induced by mRNA vaccine is crucial for anti-tumor immune response remains to be elucidated. In this study, we investigated the immunogenicity and anti-tumor responses of mRNA encoding tumor antigens with different degrees of N1-methylpseudouridine (m1Ψ) modification in B16 melanoma model. Our results demonstrated that ovalbumin (OVA) encoding mRNA formulated in a lipid nanoparticle (OVA-LNP) induced substantial IFN-I production and the maturation of dendritic cells (DCs) with negative correlation with increasing percentages of m1Ψ modification. In B16-OVA murine melanoma model, unmodified OVA-LNP significantly reduced tumor growth and prolonged survival, compared to OVA-LNP with m1Ψ modification. This robust anti-tumor effect correlated with the increase in intratumoral CD40+ DCs and the frequency of granzyme B+/IFN-γ+/TNF-α+ polyfunctional OVA peptide-specific CD8+ T cells. Blocking type I IFN receptor completely reversed the anti-tumor immunity of unmodified mRNA-OVA reflected in a significant decrease in OVA-specific IFN-γ secreting T cells and enrichment of PD-1+ tumor-infiltrating T cells. The robust anti-tumor effect of unmodified OVA-LNP was also observed in the lung metastatic tumor model. Finally, this mRNA vaccine was tested using B16 melanoma neoantigens (Pbk-Actn4) which resulted in delayed tumor growth. Taken together, our findings demonstrated that an unmodified mRNA vaccine induces IFN-I production or the downstream signaling cascades which plays a crucial role in inducing robust anti-tumor T cell response for controlling tumor growth and metastasis.
摘要：
具有未修饰核苷的mRNA通过先天性免疫传感器的刺激诱导I型干扰素(IFN-I)。mRNA疫苗诱导的IFN-I对抗肿瘤免疫应答是否至关重要尚待阐明。在这项研究中,我们在B16黑色素瘤模型中研究了编码具有不同程度的N1-甲基假尿苷（m1kW）修饰的肿瘤抗原的mRNA的免疫原性和抗肿瘤反应。我们的结果表明，在脂质纳米颗粒（OVA-LNP）中配制的卵清蛋白（OVA）编码mRNA诱导了大量的IFN-I产生和树突状细胞（DC）的成熟，并且与ml的修饰百分比呈负相关。在B16-OVA小鼠黑色素瘤模型中，未修饰的OVA-LNP显着降低肿瘤生长并延长生存期，与具有m1Φ修饰的OVA-LNP相比。这种强大的抗肿瘤作用与肿瘤内CD40DC的增加和颗粒酶B/IFN-γ/TNF-α多功能OVA肽特异性CD8T细胞的频率相关。阻断I型IFN受体完全逆转未修饰的mRNA-OVA的抗肿瘤免疫,反映在分泌OVA特异性IFN-γ的T细胞的显著减少和PD-1+肿瘤浸润性T细胞的富集。在肺转移肿瘤模型中也观察到未修饰的OVA-LNP的稳健抗肿瘤作用。最后,使用导致肿瘤生长延迟的B16黑色素瘤新抗原（Pbk-Actn4）测试了该mRNA疫苗。一起来看,我们的研究结果表明,未修饰的mRNA疫苗诱导IFN-I产生或下游信号级联反应,这在诱导强大的抗肿瘤T细胞应答以控制肿瘤生长和转移中起着至关重要的作用.
