Division of Medical Oncology, Departments of Medicine and Pathology, Stanford University, CA, Stanford, USA.
Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
J Immunother Cancer. 2018 Nov 20;6(1):125. doi: 10.1186/s40425-018-0431-x.
Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity. Treatment with IL-12-LNP significantly reduced liver tumor burden measured by dynamic magnetic resonance imaging (MRI), and increased survival of MYC-induced HCC transgenic mice in comparison to control mice. Importantly, IL-12-LNP exhibited no effect on transgenic MYC levels confirming that its therapeutic efficacy was not related to the downregulation of a driver oncogene. IL-12-LNP elicited marked infiltration of activated CD44 CD3 CD4 T helper cells into the tumor, and increased the production of Interferon γ (IFNγ). Collectively, our findings suggest that IL-12-LNP administration may be an effective immunotherapy against HCC.
白细胞介素-12 (IL-12) 是癌症免疫治疗的有前途的候选者，因为它能够激活许多识别和破坏癌细胞的宿主免疫亚群。我们发现，白细胞介素-12 (IL-12) 水平高于中位数的肝癌患者具有显著的临床获益。在这里，我们报告了一种传递白细胞介素-12 (IL-12) 的信使 RNA (mRNA) 脂质纳米颗粒 (IL-12-LNP) 可减缓 MYC 癌基因驱动的肝癌的进展。IL-12-LNP 在肝癌肿瘤内分布良好，与动物毒性无关。与对照小鼠相比，IL-12-LNP 治疗显著降低了动态磁共振成像 (MRI) 测量的肝肿瘤负担，并增加了 MYC 诱导的 HCC 转基因小鼠的存活率。重要的是，IL-12-LNP 对转基因 MYC 水平没有影响，证实其治疗效果与下调驱动癌基因无关。IL-12-LNP 引起激活的 CD44 CD3 CD4 T 辅助细胞明显浸润肿瘤，并增加了干扰素 γ (IFNγ) 的产生。总的来说，我们的研究结果表明，IL-12-LNP 给药可能是一种有效的 HCC 免疫疗法。
