RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e007068
DO 10.1136/jitc-2023-007068
VO 11
IS 6
A1 Shen, Wenhui
A1 Shi, Peishang
A1 Dong, Qingyu
A1 Zhou, Xiuman
A1 Chen, Chunxia
A1 Sui, Xinghua
A1 Tian, Wentong
A1 Zhu, Xueqin
A1 Wang, Xiaoxi
A1 Jin, Shengzhe
A1 Wu, Yahong
A1 Chen, Guanyu
A1 Qiu, Lu
A1 Zhai, Wenjie
A1 Gao, Yanfeng
YR 2023
UL http://jitc.bmj.com/content/11/6/e007068.abstract
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.