Journal Article

Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy

Jin, Shengzhe, Zhou, Xiuman, Zhou, Xiaowen, Wu, Yahong, Zhai, Wenjie, Gao, Yanfeng, Wang, Hongfei, Li, Beibei, Zhao, Wenshan, Niu, Xiaoshuang, Qi, Yuanming, Li, Yang, Wu, Menghan, Yang, Jingwen, Zhang, Xiangrui, Shi, Peishang

2024

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animals / Antibodies / Antitumor activity / B7-H1 Antigen / Biomedical and Life Sciences / Bone marrow / Cancer immunotherapy / Cancer therapies / CD47 Antigen - metabolism / CD47/SIRPα / CD8 antigen / CD8-Positive T-Lymphocytes / Cell Biology / Cell culture / Cloning / Colorectal cancer / Cytokines and Growth Factors / Flow cytometry / Immune checkpoint blockade / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immune response (cell-mediated) / Immunotherapy / L1 protein / Life Sciences / Lymphocytes T / Macrophages / Metastases / Mice / Microscopy / Neoplasms - drug therapy / Neoplasms - pathology / PD-1 protein / PD-1/PD-L1 / PD-L1 protein / Peptides / Phagocytosis / Programmed Cell Death 1 Receptor / Protein-Ligand Interactions / Proteins / Radiation therapy / Radiotherapy / Receptors / Software / Tumor Microenvironment / Tumors