2. Academic Validation
  3. 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

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

  • J Immunother Cancer. 2023 Jun;11(6):e007068. doi: 10.1136/jitc-2023-007068.
Wenhui Shen 1,  Peishang Shi 2,  Qingyu Dong 2,  Xiuman Zhou 1,  Chunxia Chen 2,  Xinghua Sui 1,  Wentong Tian 2,  Xueqin Zhu 2,  Xiaoxi Wang 2,  Shengzhe Jin 2,  Yahong Wu 2,  Guanyu Chen 1,  Lu Qiu 1,  Wenjie Zhai 3,  Yanfeng Gao 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
  • 2 School of Life Sciences, Zhengzhou University, Zhengzhou, China.
  • 3 School of Life Sciences, Zhengzhou University, Zhengzhou, China gaoyf29@mail.sysu.edu.cn wjzhai@zzu.edu.cn.
  • 4 School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China gaoyf29@mail.sysu.edu.cn wjzhai@zzu.edu.cn.
PMID: 37344099 DOI: 10.1136/jitc-2023-007068
Abstract

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.

Keywords

immunotherapy; macrophages; radiotherapy; tumor microenvironment.

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