PT  - JOURNAL ARTICLE
AU  - Shen, Wenhui
AU  - Shi, Peishang
AU  - Dong, Qingyu
AU  - Zhou, Xiuman
AU  - Chen, Chunxia
AU  - Sui, Xinghua
AU  - Tian, Wentong
AU  - Zhu, Xueqin
AU  - Wang, Xiaoxi
AU  - Jin, Shengzhe
AU  - Wu, Yahong
AU  - Chen, Guanyu
AU  - Qiu, Lu
AU  - Zhai, Wenjie
AU  - Gao, Yanfeng
TI  - Discovery of a novel dual-targeting D-peptide to block CD24/Siglec-10 and PD-1/PD-L1 interaction and synergize with radiotherapy for cancer immunotherapy
AID  - 10.1136/jitc-2023-007068
DP  - 2023 Jun 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e007068
VI  - 11
IP  - 6
4099  - http://jitc.bmj.com/content/11/6/e007068.short
4100  - http://jitc.bmj.com/content/11/6/e007068.full
SO  - J Immunother Cancer2023 Jun 01; 11
AB  - 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.Data are available upon reasonable request.