Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-024-01555-4 |
| _version_ | 1797259185821319168 |
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| author | Shengzhe Jin Hongfei Wang Yang Li Jingwen Yang Beibei Li Peishang Shi Xiangrui Zhang Xiaowen Zhou Xiuman Zhou Xiaoshuang Niu Menghan Wu Yahong Wu Wenjie Zhai Yuanming Qi Yanfeng Gao Wenshan Zhao |
| author_facet | Shengzhe Jin Hongfei Wang Yang Li Jingwen Yang Beibei Li Peishang Shi Xiangrui Zhang Xiaowen Zhou Xiuman Zhou Xiaoshuang Niu Menghan Wu Yahong Wu Wenjie Zhai Yuanming Qi Yanfeng Gao Wenshan Zhao |
| author_sort | Shengzhe Jin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T23:05:25Z |
| format | Article |
| id | doaj.art-e691f26caa4b41538892947c9f03fbbd |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-04-24T23:05:25Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-e691f26caa4b41538892947c9f03fbbd2024-03-17T12:33:10ZengBMCCell Communication and Signaling1478-811X2024-03-0122111610.1186/s12964-024-01555-4Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapyShengzhe Jin0Hongfei Wang1Yang Li2Jingwen Yang3Beibei Li4Peishang Shi5Xiangrui Zhang6Xiaowen Zhou7Xiuman Zhou8Xiaoshuang Niu9Menghan Wu10Yahong Wu11Wenjie Zhai12Yuanming Qi13Yanfeng Gao14Wenshan Zhao15School of Life Sciences, Zhengzhou UniversityHenan Key Laboratory of Immunology and Targeted Drugs, School of Medical Technology, Xinxiang Medical UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen UniversitySchool of Life Sciences, Zhengzhou UniversityAbstract 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.https://doi.org/10.1186/s12964-024-01555-4Tumor microenvironmentImmune checkpoint blockadePD-1/PD-L1CD47/SIRPαRadiotherapy |
| spellingShingle | Shengzhe Jin Hongfei Wang Yang Li Jingwen Yang Beibei Li Peishang Shi Xiangrui Zhang Xiaowen Zhou Xiuman Zhou Xiaoshuang Niu Menghan Wu Yahong Wu Wenjie Zhai Yuanming Qi Yanfeng Gao Wenshan Zhao Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy Cell Communication and Signaling Tumor microenvironment Immune checkpoint blockade PD-1/PD-L1 CD47/SIRPα Radiotherapy |
| title | Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy |
| title_full | Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy |
| title_fullStr | Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy |
| title_full_unstemmed | Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy |
| title_short | Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy |
| title_sort | discovery of a novel small molecule as cd47 sirpα and pd 1 pd l1 dual inhibitor for cancer immunotherapy |
| topic | Tumor microenvironment Immune checkpoint blockade PD-1/PD-L1 CD47/SIRPα Radiotherapy |
| url | https://doi.org/10.1186/s12964-024-01555-4 |
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