anti-human CD3 (OKT3); anti-human CD28 (CD28.2) ; BioGems ;
Cell Commun Signal. 2024 Mar 11;22(1):173. doi: 10.1186/s12964-024-01555-4.
Shengzhe Jin # 1, Hongfei Wang # 2, Yang Li # 1, Jingwen Yang 1, Beibei Li 1, Peishang Shi 1, Xiangrui Zhang 1, Xiaowen Zhou 1, Xiuman Zhou 3, Xiaoshuang Niu 3, Menghan Wu 1, Yahong Wu 1 4, Wenjie Zhai 1 4, Yuanming Qi 1, Yanfeng Gao 5, Wenshan Zhao 6
Affiliations expand
- PMID: 38462636
- PMCID: PMC10926604
- DOI: 10.1186/s12964-024-01555-4
Abstract
Background: Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative.
Methods: SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model.
Results: SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8+ T and M1-type macrophages into tumor sites, while also priming the function of CD8+ T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy.
Conclusion: Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy.