TLR7/8 signaling activation enhances the potency of human pluripotent stem cell-derived eosinophils in cancer immunotherapy for solid tumors.

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Tác giả: Chenyi Dai, Hongkui Deng, Ruixin Gu, Yi Huo, Qi Lei, Cheng Li, Tianxing Liu, Lejun Lv, Yudi Miao, Chengyan Wang, Guokai Wang, Ming Yin, Jinghao You, Yingfeng Zhang, Zixin Zhao, Zhengyang Zhou, Sheng Zhu

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: England : Experimental hematology & oncology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 741650

BACKGROUND: Efficient tumor T-cell infiltration is crucial for the effectiveness of T-cell-based therapies against solid tumors. Eosinophils play crucial roles in recruiting T cells in solid tumors. Our group has previously generated induced eosinophils (iEOs) from human pluripotent stem cells and exhibited synergistic efficacy with CAR-T cells in solid tumor inhibition. However, administrated eosinophils might influx into inflammatory lungs, posing a potential safety risk. Mitigating the safety concern and enhancing efficacy is a promising development direction for further application of eosinophils. METHODS: We developed a new approach to generate eosinophils with enhanced potency from human chemically reprogrammed induced pluripotent stem cells (hCiPSCs) with the Toll-like receptor (TLR) 7/8 signaling agonist R848. RESULTS: R848-activated iEOs (R-iEOs) showed significantly decreased influx to the inflamed lungs, indicating a lower risk of causing airway disorders. Furthermore, these R-iEOs had enhanced anti-tumor functions, preferably accumulated at tumor sites, and further increased T-cell infiltration. The combination of R-iEOs and CAR-T cells suppressed tumor growth in mice. Moreover, the chemo-trafficking signaling increased in R-iEOs, which may contribute to the decreased lung influx of R-iEOs and the increased tumor recruitment of T cells. CONCLUSION: Our study provides a novel approach to alleviate the potential safety concerns associated with eosinophils while increasing T-cell infiltration in solid tumors. This finding offers a prospective strategy for incorporating eosinophils to improve CAR-T-cell immunotherapy for solid tumors in the future.
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