Johns Hopkins University, School of Medicine, Department of Medicine, Center for Tuberculosis Research, Baltimore, MD, USA.
The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA.
Nat Commun. 2022 Feb 15;13(1):878. doi: 10.1038/s41467-022-28509-z.
In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING). We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher pro-inflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhances epigenetic and metabolomic changes. In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality. These results indicate that trained immunity levels and antitumor efficacy may be increased by modifying BCG to express higher levels of key PAMP molecules.
除了作为结核病疫苗外，卡介苗还通过一种称为训练免疫的过程显示出对许多其他病原体（包括病毒）产生异源保护作用。尽管卡介苗具有广泛保护作用的潜力，但几乎没有做任何工作来确定卡介苗介导的训练免疫水平是否可以优化。在这里，我们重新设计卡介苗来表达高水平的 c-di-AMP，这是一种被干扰素基因刺激物 (STING) 识别的 PAMP。我们发现，表达 c-di-AMP 的卡介苗引发了更强烈的训练免疫特征，包括更高的促炎细胞因子反应、向炎症和激活状态的髓样细胞重编程更大，以及增强了表观遗传和代谢组学变化。在膀胱癌模型中，我们还表明，经过重新设计的卡介苗可诱导训练免疫并提高功能。这些结果表明，通过修饰卡介苗来表达更高水平的关键 PAMP 分子，可能会增加训练免疫水平和抗肿瘤疗效。
