肿瘤微环境
癌症研究
免疫检查点
免疫疗法
西格莱克
癌症免疫疗法
免疫系统
癌细胞
T细胞
癌症
化学
医学
免疫学
内科学
作者
Wenhui Shen,Peishang Shi,Qingyu Dong,Xiaoxi Zhou,Chunxia Chen,Xinghua Sui,W. Tian,Xueqiong Zhu,Xiaoxi Wang,Shengzhe Jin,WU Yi-ming,Guan-Yu Chen,Lu Qiu,Wenjie Zhai,Yanfeng Gao
标识
DOI:10.1136/jitc-2023-007068
摘要
Background Aside from immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), intervention of CD47/Sirpα mediated ‘don’t eat me’ signal between macrophage and tumor cell is considered as a promising therapeutic approach for cancer immunotherapy. Compared with CD47, the novel immune checkpoint CD24/Siglec-10 can also deliver ‘don’t eat me’ signal and CD24 shows much lower expression level in normal tissue which might avoid unwanted side effects. Methods Cell-based phage display biopanning and D-amino acid modification strategy were used to identify the CD24/Siglec-10 blocking peptide. Cell-based blocking assay and microscale thermophoresis assay were used to validate the blocking and binding activities of the peptide. Phagocytosis and co-culture assays were used to explore the in vitro function of the peptide. Flow cytometry was performed to assess the immune microenvironment after the peptide treatment in vivo. Results A CD24/Siglec-10 blocking peptide (CSBP) with hydrolysis-resistant property was identified. Surprisingly, we found that CSBP could not only block the interaction of CD24/Siglec-10 but also PD-1/PD-L1. CSBP could induce the phagocytosis of tumor cell by both the macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs), which can further activate CD8 + T cells. Besides, combination of radiotherapy and CSBP synergistically reduced tumor growth and altered the tumor microenvironment in both anti-PD-1-responsive MC38 and anti-PD-1-resistant 4T1 tumor models. Conclusions In summary, this is the first CD24/Siglec-10 blocking peptide which blocked PD-1/PD-L1 interaction as well, functioned via enhancing the phagocytosis of tumor cells by macrophages and M-MDSCs, and elevating the activity of CD8 + T cells for cancer immunotherapy.
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