Immune-enhancing neutrophils reprogrammed by subclinical low-dose endotoxin in cancer treatment

作者：Yao Zhang, Christina Lee, Shuo Geng, Jing Wang, Udipta Bohara, Jacqueline Hou, Ziyue Yi, Liwu Li · 发表于：EMBO Molecular Medicine · 年份：2024 · DOI：10.1038/s44321-024-00100-7 · 被引用次数：7 · 研究领域：Immune cells in cancer、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

Abstract 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 CD177 lo CD11b lo CD80 hi CD40 hi Dectin2 hi . 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.