Cancer immunotherapy is a powerful approach for cancer treatment, but its clinical effects rely on the tumor's immune conditions. In particular, low response rates to PD-1 blockades are highly correlated with impaired T cell priming. Here, we demonstrate that E. coli-derived monophosphoryl lipid A (EcML) activates dendritic cells in a toll-like receptor-4 (TLR-4)-dependent manner and increases the sensitivity of cancer cells to anti-PD-1 immunotherapy. EcML is a mixture of 4'-monophosphoryl lipids A (MPLAs) produced directly by an engineered Escherichia coli strain; it has a unique congener composition that differentiates it from the well-established MPLA adjuvants, 3-O-desacyl-4'-monophosphoryl lipid A and glucopyranosyl lipid A. Given that active dendritic cells initiate adaptive immune responses, we investigated the anti-tumor activity of an aqueous formulation of EcML. Upon sensing EcML via TLR-4, dendritic cells matured into powerful antigen-presenting cells that could stimulate naïve T cells. EcML reduced tumor growth in the B16F10 mouse model via dendritic cell activation and potentiated PD-1 blockade therapy in the B16F10-OVA melanoma model. These data identify EcML as a promising TLR-4 agonist that can induce anti-tumor immune responses and potentiate PD-1 blockade therapy against tumors.

中文翻译：

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大肠杆菌来源的单磷酰脂质A对树突状细胞的激活增强了PD-1阻断的功效。

癌症免疫疗法是一种强大的癌症治疗方法，但其临床效果取决于肿瘤的免疫状况。特别是，对PD-1阻滞的低应答率与受损的T细胞启动密切相关。在这里，我们证明了大肠杆菌来源的单磷酰脂质A（EcML）以toll样受体4（TLR-4）依赖的方式激活树突状细胞，并增加了癌细胞对PD-1免疫疗法的敏感性。EcML是由工程化大肠杆菌菌株直接产生的4'-单磷酰基脂质A（MPLA）的混合物；它具有独特的同类物成分，可与完善的MPLA佐剂，3-O-去酰基-4'-单磷酰基脂质A和吡喃葡萄糖基脂质A区别开来。鉴于活跃的树突状细胞会启动适应性免疫反应，我们研究了EcML的水性制剂的抗肿瘤活性。通过TLR-4感应EcML后，树突状细胞成熟为强大的抗原呈递细胞，可以刺激幼稚T细胞。EcML通过树突状细胞激活和B16F10-OVA黑色素瘤模型中的有效PD-1阻断疗法降低了B16F10小鼠模型中的肿瘤生长。这些数据确定EcML是一种有前途的TLR-4激动剂，可以诱导抗肿瘤免疫反应并增强针对肿瘤的PD-1阻断疗法。