Despite the re-emergence of the pioneering "Coley's toxin" concept in anti-cancer immune therapies highlighted by check-point inhibitors and CAR-T approaches, fundamental mechanisms responsible for the immune-enhancing efficacy of low-dose "Coley's toxin" remain poorly understood. This study examines the novel reprogramming of immune-enhancing neutrophils by super-low dose endotoxin conducive for anti-cancer therapies. Through integrated analyses including scRNAseq and functional characterizations, we examined the efficacy of reprogrammed neutrophils in treating experimental cancer. We observed that neutrophils trained by super-low dose endotoxin adopt a potent immune-enhancing phenotype characterized by CD177loCD11bloCD80hiCD40hiDectin2hi. Both murine and human neutrophils trained by super-low dose endotoxin exhibit relieved suppression of adaptive T cells as compared to un-trained neutrophils. Functionally, neutrophils trained by super-low dose endotoxin can potently reduce tumor burden when transfused into recipient tumor-bearing mice. Mechanistically, Super-low dose endotoxin enables the generation of immune-enhancing neutrophils through activating STAT5 and reducing innate suppressor IRAK-M. Together, our data clarify the long-held mystery of "Coley's toxin" in rejuvenating anti-tumor immune defense, and provide a proof-of-concept in developing innate neutrophil-based anti-tumor therapeutics.

中文翻译：

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在癌症治疗中通过亚临床低剂量内毒素重新编程免疫增强中性粒细胞。


尽管在检查点抑制剂和CAR-T方法的推动下，开创性的“Coley氏毒素”概念在抗癌免疫疗法中重新出现，但负责低剂量“Coley氏毒素”免疫增强功效的基本机制仍然很差。明白了。这项研究探讨了超低剂量内毒素对免疫增强中性粒细胞的新型重编程，有利于抗癌治疗。通过包括 scRNAseq 和功能表征在内的综合分析，我们检查了重编程中性粒细胞在治疗实验性癌症中的功效。我们观察到，经过超低剂量内毒素训练的中性粒细胞采用了以 CD177loCD11bloCD80hiCD40hiDectin2hi 为特征的有效免疫增强表型。与未经训练的中性粒细胞相比，经过超低剂量内毒素训练的小鼠和人类中性粒细胞均表现出对适应性 T 细胞的抑制减轻。从功能上讲，经过超低剂量内毒素训练的中性粒细胞在输注到荷瘤小鼠体内时可以有效减轻肿瘤负荷。从机制上讲，超低剂量内毒素可通过激活 STAT5 和减少先天抑制因子 IRAK-M 来产生免疫增强中性粒细胞。总之，我们的数据澄清了“科利毒素”在恢复抗肿瘤免疫防御方面长期以来的谜团，并为开发基于先天性中性粒细胞的抗肿瘤疗法提供了概念验证。